Publications by authors named "Ha-Na Lee"

76 Publications

Nuclear Factor Erythroid 2-related Factor 2 Knockout Suppresses the Development of Aggressive Colorectal Cancer Formation Induced by Azoxymethane/Dextran Sulfate Sodium-Treatment in Female Mice.

J Cancer Prev 2021 Mar;26(1):41-53

Laboratory of Immunology, Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.

Colon tumors develop more frequently in male than in female. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays differential roles in the stage of tumorigenesis. The purpose of this study was to investigate the role of Nrf2 on colitis-associated tumorigenesis using Nrf2 knockout (KO) female mice. Azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated wild-type (WT) and Nrf2 KO female mice were sacrificed at week 2 and 16 after AOM injection. Severity of colitis, tumor incidence, and levels of inflammatory mediators were evaluated in AOM/DSS-treated WT and Nrf2 KO mice. Furthermore, qRT-PCR, Western blot abnalysis, and ELISA were performed in colon tissues. At week 2, AOM/DSS-induced colon tissue damages were significantly greater in Nrf2 KO than in WT mice. At week 16, tumor numbers (> 2 mm size) were significantly lower in both the proximal and distal colon in Nrf2 KO compared to WT. The overall incidences of adenoma/cancer of the proximal colon and submucosal invasive cancer of the distal colon were reduced by Nrf2 KO. The mRNA and protein expression levels of NF-κB-related mediators (i.e., iNOS and COX-2) and Nrf2-related antioxidants (i.e., heme oxygenase-1 and glutamate-cysteine ligase catalytic subunit) were significantly lower in the Nrf2 KO than in WT mice. Interestingly, the protein level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) was higher in AOM/DSS-treated Nrf2 KO than in WT mice. Our results support the oncogenic effect of Nrf2 in the later stage of carcinogenesis and upregulation of tumor suppressor 15-PGDH might contribute to the repression of colitis-associated tumorigenesis in Nrf2 KO female mice.
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http://dx.doi.org/10.15430/JCP.2021.26.1.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020176PMC
March 2021

Resolvin D1 suppresses inflammation-associated tumorigenesis in the colon by inhibiting IL-6-induced mitotic spindle abnormality.

FASEB J 2021 May;35(5):e21432

Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.

While failure in resolution of inflammation is considered to increase the risk of tumorigenesis, there is paucity of experimental as well as clinical evidence supporting this association. Resolvin D1 (RvD1) is a representative pro-resolving lipid mediator that is endogenously generated from docosahexaenoic acid for the resolution of inflammation. Here, we report a decreased level of RvD1 in the blood from colorectal cancer patients and mice having inflammation-induced colon cancer, suggesting plasma RvD1 as a potential biomarker for monitoring colorectal cancer. Administration of RvD1 attenuated dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM) plus DSS-induced colorectal carcinogenesis by suppressing the production of interleukin-6 (IL-6) and IL-6-mediated chromosomal instability. The protective effect of RvD1 against chromosomal instability is associated with downregulation of IL-6-induced Cyclin D1 expression, which appears to be mediated by blocking the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) axis. RvD1 inhibited the STAT3 signaling pathway by interfering with the binding of IL-6 to its receptor (IL-6R), suggesting the novel function of RvD1 as a putative IL-6R antagonist. Together, our findings suggest that RvD1-mediated blockade of IL-6 signal transmission may contribute to inhibition of chromosomal instability and tumorigenesis.
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http://dx.doi.org/10.1096/fj.202002392RDOI Listing
May 2021

Long-term persistence of infectious Zika virus: Inflammation and behavioral sequela in mice.

PLoS Pathog 2020 12 10;16(12):e1008689. Epub 2020 Dec 10.

US Food and Drug Administration, Office of Biotechnology Products, Silver Spring, Maryland, United States of America.

The neurodevelopmental defects associated with ZIKV infections early in pregnancy are well documented, however the potential defects and long-term consequences associated with milder infections in late pregnancy and perinatal period are less well understood. To model these, we challenged 1 day old (P1) immunocompetent C57BL/6 mice with ZIKV. The animals developed a transient neurological syndrome including unsteady gait, kinetic tremors, severe ataxia and seizures 10-15 days post-infection (dpi) but symptoms subsided after a week, and most animals survived. Despite apparent recovery, MRI of convalescent mice show reduced cerebellar volume that correlates with altered coordination and motor function as well as hyperactivity and impulsivity. Persistent mRNA levels of pro-inflammatory genes including Cd80, Il-1α, and Ifn-γ together with Cd3, Cd8 and perforin (PrfA), suggested persistence of low-grade inflammation. Surprisingly, the brain parenchyma of convalescent mice harbor multiple small discrete foci with viral antigen, active apoptotic processes in neurons, and cellular infiltrates, surrounded by activated astrocytes and microglia as late as 1-year post-infection. Detection of negative-sense strand viral RNA and isolation of infectious virus derived from these convalescent mice by blinded passage in Vero cells confirmed long-term persistence of replicating ZIKV in CNS of convalescent mice. Although the infection appears to persist in defined reservoirs within CNS, the resulting inflammation could increase the risk of neurodegenerative disorders. This raises concern regarding possible long-term effects in asymptomatic children exposed to the virus and suggests that long-term neurological and behavioral monitoring as well as anti-viral treatment to clear virus from the CNS may be useful in patients exposed to ZIKV at an early age.
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http://dx.doi.org/10.1371/journal.ppat.1008689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728251PMC
December 2020

Bilateral pneumothorax in a patient with anaplastic thyroid carcinoma and lung metastasis during lenvatinib therapy: a case report.

Gland Surg 2020 Oct;9(5):1579-1583

Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Hanyang University, Seoul, Republic of Korea.

The prognosis of anaplastic thyroid carcinoma (ATC) is very poor. In most patients, ATC presents with cervical lymph node metastasis, and more than 40% of patients have distant metastasis at the time of diagnosis. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, is a novel drug that has antitumor effects on radioactive iodine-refractory papillary cancer and anaplastic cancer. The development of bilateral pneumothorax during targeted therapy is very rare in patients with thyroid cancer. We recently encountered a case of bilateral pneumothorax in a patient with ATC and lung metastasis during lenvatinib therapy. The patient underwent video-assisted thoracoscopic surgery (VATS) in both the lungs because the pneumothorax continued to aggravate even after the insertion of chest tubes. Clinicians need to be aware that the development of pneumothorax is a possibility during lenvatinib therapy for ATC and lung metastasis. The case is reported herein, along with a review of relevant literature.
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http://dx.doi.org/10.21037/gs-20-462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667081PMC
October 2020

17β-Estradiol strongly inhibits azoxymethane/dextran sulfate sodium-induced colorectal cancer development in Nrf2 knockout male mice.

Biochem Pharmacol 2020 12 15;182:114279. Epub 2020 Oct 15.

Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, South Korea.

Nuclear factor erythroid 2-related factor 2 (Nrf2) has dual effects on inflammation and cancer progression depending on the microenvironment. Estrogens have a protective effect on colorectal cancer (CRC) development. The aim of this study was to investigate CRC development in Nrf2 knockout (KO) mice. Azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated wild-type (WT) and Nrf2 KO male mice were sacrificed at weeks 2 and 16 after AOM injection with/without 17β-estradiol (E2) treatment during week 1. Disease activity index and colon tissue damage at week 2 showed strong attenuation following E2 administration in WT mice but to a lesser extent in Nrf2 KO male mice. At week 16, E2 significantly diminished AOM/DSS-induced adenoma/cancer incidence at distal colon in the Nrf2 KO group, but not in the WT. Furthermore, mRNA or protein levels of NF-κB-related mediators (i.e., iNOS, TNF-α, and IL-1β) and Nrf2-related antioxidants (i.e., NQO1 and HO-1) were significantly lower in the Nrf2 KO group regardless of E2 treatment compared to the WT. The expression of estrogen receptor beta (ERβ) was higher in the Nrf2 KO group than in the WT. In conclusion, estrogen further inhibits CRC by upregulating ERβ-related alternate pathways in the absence of Nrf2.
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http://dx.doi.org/10.1016/j.bcp.2020.114279DOI Listing
December 2020

Helicobacter pylori infection induces STAT3 phosphorylation on Ser727 and autophagy in human gastric epithelial cells and mouse stomach.

Sci Rep 2020 09 24;10(1):15711. Epub 2020 Sep 24.

Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea.

Helicobacter pylori (H. pylori) infection is considered as one of the principal risk factors of gastric cancer. Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) plays an important role in inflammation-associated gastric carcinogenesis. In the canonical STAT3 pathway, phosphorylation of STAT3 on Tyr705 is a major event of STAT3 activation. However, recent studies have demonstrated that STAT3 phosphorylated on Ser727 has an independent function in mitochondria. In the present study, we found that human gastric epithelial AGS cells infected with H. pylori resulted in localization of STAT3 phosphorylated on Ser727 (P-STAT3), predominantly in the mitochondria. Notably, H. pylori-infected AGS cells exhibited the loss of mitochondrial integrity and increased expression of the microtubule-associated protein light chain 3 (LC3), the autophagosomal membrane-associated protein. Treatment of AGS cells with a mitophagy inducer, carbonyl cyanide 3-chlorophenylhydrazone (CCCP), resulted in accumulation of P-STAT3 in mitochondria. In addition, the elevated expression and mitochondrial localization of LC3 induced by H. pylori infection were attenuated in AGS cells harboring STAT3 mutation defective in Ser727 phosphorylation (S727A). We also observed that both P-STAT3 expression and LC3 accumulation were increased in the mitochondria of H. pylori-inoculated mouse stomach.
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http://dx.doi.org/10.1038/s41598-020-72594-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519032PMC
September 2020

Treatment Strategy for Odontogenic Sinusitis.

Am J Rhinol Allergy 2021 Mar 28;35(2):206-212. Epub 2020 Jul 28.

Department of Otolaryngology-Head and Neck Surgery, Hanyang University College of Medicine, Seoul, Korea.

Background: The treatment options for odontogenic sinusitis (OS) include medical management including antibiotics and saline nasal irrigation, endoscopic sinus surgery (ESS), and dental treatment.

Objective: The purpose of this study was to evaluate whether OS caused by dental caries and periapical abscess can be cured by dental treatment alone and which patients should consider surgery early.

Methods: A total of 33 patients with OS caused by dental caries and periapical abscess were enrolled. Patients with OS caused by dental implants, trauma, surgery, or tooth extraction were excluded. All patients were initially treated with dental treatment and medical management without ESS. The patients were divided into two groups according to the results of dental treatment and multiple clinical parameters were compared between the two groups.

Results: Among the 33 enrolled patients, 22 patients (67%) were cured with dental and medical management, and 11 patients (33%) required ESS after the failure of dental and medical management. Based on the multivariate analysis results, patients who were smokers (OR 33.4) and had a higher Lund-Mackay score on CT (OR 2.0) required ESS after the failure of dental and medical treatment.

Conclusions: Two-thirds of the patients with OS caused by dental caries and periapical abscess were cured with dental treatment and medical management without ESS. We recommend dental treatment and medical management first in OS caused by dental caries and periapical abscess. However, we recommend early ESS in patients with smoking habits and severe CT findings of the sinus.
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http://dx.doi.org/10.1177/1945892420946969DOI Listing
March 2021

17β-Estradiol supplementation changes gut microbiota diversity in intact and colorectal cancer-induced ICR male mice.

Sci Rep 2020 07 23;10(1):12283. Epub 2020 Jul 23.

Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, South Korea.

The composition of the gut microbiota is influenced by sex hormones and colorectal cancer (CRC). Previously, we reported that 17β-estradiol (E2) inhibits azoxymethane/dextran sulfate sodium (AOM/DSS)-induced tumorigenesis in male mice. Here, we investigated whether the composition of the gut microbiota is different between male and female, and is regulated by estrogen as a secondary outcome of previous studies. We established four groups of mice based on the sex and estrogen status [ovariectomized (OVX) female and E2-treated male]. Additionally, three groups of males were established by treating them with AOM/DSS, and E2, after subjecting them to AOM/DSS treatment. The mice were sacrificed at 21 weeks old. The composition of the gut microbiota was analyzed using 16S rRNA metagenomics sequencing. We observed a significant increase in the microbial diversity (Chao1 index) in females, males supplemented with E2, and males treated with AOM/DSS/E2 compared with normal males. In normal physiological condition, sex difference and E2 treatment did not affect the ratio of Firmicutes/Bacteroidetes (F/B). However, in AOM/DSS-treated male mice, E2 supplementation showed significantly lower level of the F/B ratio. The ratio of commensal bacteria to opportunistic pathogens was higher in females and E2-treated males compared to normal males and females subjected to OVX. Unexpectedly, this ratio was higher in the AOM/DSS group than that determined in other males and the AOM/DSS/E2 group. Our findings suggest that estrogen alters the gut microbiota in ICR (CrljOri:CD1) mice, particularly AOM/DSS-treated males, by decreasing the F/B ratio and changing Shannon and Simpson index by supply of estrogen. This highlights another possibility that estrogen could cause changes in the gut microbiota, thereby reducing the risk of developing CRC.
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http://dx.doi.org/10.1038/s41598-020-69112-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378548PMC
July 2020

Transcultural Adaptation and Validation of the Korean Version of the Vocal Tract Discomfort Scale.

J Voice 2020 Jun 20. Epub 2020 Jun 20.

Department of Otorhinolaryngology - Head and Neck Surgery, Chosun University College of Medicine, Gwangju, South Korea. Electronic address:

Objectives: The present study translated the Vocal Tract Discomfort Scale (VTDS) into Korean (K-VTDS) and evaluated its reliability and validity.

Study Design: This was a prospective study.

Methods: The VTDS was first translated into Korean and validated. One hundred and fifty-nine patients with voice disorders were divided into three different diagnostic groups (functional, structural, and neurologic voice disorder) and 131 vocally healthy adults were also included. All participants completed the K-VTDS and the Korean version of the Voice Handicap Index (K-VHI) and Korean versions of the Voice-Related Quality of Life (K-VRQOL). The internal consistency of the K-VTDS was analyzed through Cronbach's α coefficient. The VTDS score differences related to the diagnostic groups were assessed with t test and analysis of variance. We assessed the correlation between the K-VTDS, the K-VHI, and the K-VRQOL using Pearson's correlation analysis.

Results: High internal consistency and the test-retest reliability of the K-VTDS were found. The voice disorder group had significantly higher K-VTDS scores for the subscales and total scores than those in the healthy group (P < 0.001). The K-VTDS scores for the subscale of frequency and total scores were highest in the functional voice disorder group. We found a significant difference in frequency and total score of the K-VTDS between the functional voice disorder group and the structural voice disorder group (P < 0.05). We observed a strong positive correlation among the scores for the subscales of frequency and severity, and total scores in the K-VTDS. The K-VTDS showed moderate correlation with the K-VHI and the K-VRQOL.

Conclusion: The K-VTDS is a reliable and valid instrument for voice assessment for voice disorders in Korean-speaking patients.
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http://dx.doi.org/10.1016/j.jvoice.2020.04.030DOI Listing
June 2020

Korean Translation and Linguistic Validation of Urgency and Overactive Bladder Questionnaires.

Int Neurourol J 2020 Mar 31;24(1):66-76. Epub 2020 Mar 31.

Department of Urology, Seoul National University Hospital, Seoul, Korea.

Purpose: Given the importance of evaluating the severity of overactive bladder (OAB) symptoms and outcomes after treatment, several questionnaires have been developed to evaluate OAB patients. However, only limited questionnaires are available in Korea for use with Korean patients. Therefore, this study aimed to develop Korean versions of OAB questionnaires through a rigorous linguistic validation process.

Methods: The Indevus Urgency Severity Scale, Urgency Perception Scale, Urgency Severity Scale, and Patient Perception of Intensity of Urgency Scale underwent translation and linguistic validation. The linguistic validation procedure consisted of permission for translation, forward translations, reconciliation, back-translation, cognitive debriefing, and proofreading. Two independent bilingual translators translated the original version of each questionnaire, and a panel then discussed and reconciled the 2 initial translations. Next, a third independent bilingual translator performed a backward translation of the reconciled version into English. Five Korean patients diagnosed with OAB were interviewed for cognitive debriefing.

Results: Each item of the questionnaires was translated into 2 Korean versions in the forward translation process. Terms such as 'urgency' and 'wetting' were translated into ordinary language by the translators and adjusted by the panel members to more conceptually equivalent terms in a medical context. In the back-translation process, the panel made a few changes regarding details based on a comparison of the back-translated and original versions. During the cognitive debriefing process, 5 patients provided a few pieces of feedback on the naturalness of the wording of the questionnaires, but generally agreed on the translated terms.

Conclusion: In this study, the panel produced a successful linguistic validation of Korean versions of multiple OAB questionnaires, which can be utilized to evaluate the severity and treatment outcomes of OAB.
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http://dx.doi.org/10.5213/inj.1938164.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136437PMC
March 2020

17-β estradiol exerts anti-inflammatory effects through activation of Nrf2 in mouse embryonic fibroblasts.

PLoS One 2019 23;14(8):e0221650. Epub 2019 Aug 23.

Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.

Several reports indicate crosstalk between the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and estrogen, which has a protective effect in colorectal cancer (CRC). The aim of this study was to investigate the role of Nrf2 signaling in the anti-inflammatory effect of estrogen using Nrf2 knockout (Nrf2 KO) mouse embryonic fibroblasts (MEFs), a powerful system to test the function of target genes due to their easy accessibility, and rapid growth rates. After inducing inflammation by tumor necrosis factor alpha (TNF-α), the effects of 17β-estradiol (E2) on the expression of proinflammatory mediators [i.e., NF-κB and inducible nitric oxide synthase (iNOS)] and estrogen receptors were evaluated by Western blot. In wild type (WT) MEFs, E2 treatment ameliorated TNF-α-induced nuclear translocation of NF-κB and expression of its target protein iNOS. Estrogen receptor beta (ERβ) expression was decreased by TNF-α-induced inflammation and restored by E2 treatment. When treated to WT MEFs, E2 induced nuclear translocation of Nrf2. The inhibitory effect of E2 on TNF-α-induced enhancement of iNOS was markedly dampened in Nrf2 KO MEFs. Notably, ERβ expression was significantly diminished in Nrf2 KO MEFs compared to that in WT cells. Promoter Database (EPD) revealed two putative anti-oxidant response elements (AREs) within the mouse ERβ promoter. Furthermore, in WT MEFs, E2 treatment repressed TNF-α-induced expression of iNOS protein and recovered by 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol (PHTPP), a selective ERβ antagonist, treatment, but not in Nrf2 KO MEFs. In conclusion, Nrf2 plays a pivotal role in the anti-inflammatory of estrogen by direct regulating the expression of ERβ.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221650PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707591PMC
March 2020

Effects of 17β-estradiol on colorectal cancer development after azoxymethane/dextran sulfate sodium treatment of ovariectomized mice.

Biochem Pharmacol 2019 06 11;164:139-151. Epub 2019 Apr 11.

Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, South Korea.

Estrogen is known to have a protective effect in colorectal cancer (CRC) development. Previously, we reported the anti-inflammatory and antitumorigenic effects of 17β-estradiol (E2) in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated male mice. The aim of this study was to investigate whether ovariectomy in a female AOM/DSS mouse model increases colorectal tumorigenesis and whether tumorigenesis is reduced by estrogen supplementation after ovariectomy. Clinical symptoms and histological severity of colitis and the levels of inflammatory mediators were evaluated in the colon of AOM/DSS-treated ovariectomized (OVX) mice. The levels of E2, myeloperoxidase (MPO), and NF-κB-dependent cytokines (interleukin (IL)-1β and IL-6) were measured by ELISA. Furthermore, quantitative real-time (qRT) PCR and Western blot analysis were performed. Ovariectomy did not aggravate AOM/DSS-induced colitis at 2 weeks. At weeks 10 and 16, ovariectomy significantly increased tumor number and incidence rate in only the proximal colon after AOM/DSS treatment (F_AOM/DSS vs OVX_AOM/DSS), and these increases were significantly reduced by E2 supplementation (OVX_AOM/DSS vs OVX_AOM/DSS/E2). However, ovariectomy did not affect CRC development in the distal colon (F_AOM/DSS vs OVX_AOM/DSS). At week 2, E2 administration to AOM/DSS-treated OVX mice attenuated the histological severity of colitis by decreasing the protein and/or mRNA levels of estrogen receptor alpha (ERα) and NF-κB-related mediators (i.e., COX-2, TNF-α, and IL-6) and by enhancing estrogen receptor beta (ERβ) and nuclear Nrf2 protein expression and the mRNA expression of related antioxidant enzyme genes (i.e., HO-1, GCLC, GCLM, and NQO1). Endogenous estrogen in females protects against the development of proximal colon cancer, and exogenous E2 replacement in OVX female mice showed protective effects against AOM/DSS-induced colitis and carcinogenesis. The mechanism could involve modulating ERs-, NF-κB- and Nrf2-mediated pathways.
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http://dx.doi.org/10.1016/j.bcp.2019.04.011DOI Listing
June 2019

15-Deoxy-Δ-prostaglandin J up-regulates the expression of 15-hydroxyprostaglandin dehydrogenase through DNA methyltransferase 1 inactivation.

Free Radic Res 2019 Mar 1;53(3):335-347. Epub 2019 Mar 1.

c Department of Food and Nutrition, College of Health & Wellness , Sungshin Women's University , Seoul , South Korea.

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyses the conversion of prostaglandin E to a keto metabolite. The expression of 15-PGDH is ubiquitously repressed in various human malignancies. However, the molecular mechanisms underlying down-regulation of 15-PGDH expression remain largely unknown. 15-Deoxy-△-prostaglandin J (15d-PGJ), an endogenous ligand of peroxisome proliferator-activated receptor γ, has been reported to have anti-inflammatory and anticarcinogenic activities. In the present study, we have found that 15d-PGJ induces expression and catalytic activity of 15-PGDH in human breast cancer (MDA-MB-231) cells. 15d-PGJ decreased the level of CpG methylation in the 15-PGDH promoter in MDA-MB-231 cells as determined by the bisulphite genome sequencing and methyl-specific PCR. 15d-PGJ inhibited the catalytic activity of methyltransferase 1 (DNMT1) but did not influence its expression. Biotinylated 15d-PGJ directly interacted with DNMT1 and reduced its catalytic activity. Chromatin-immunoprecipitation analysis revealed that 15d-PGJ significantly attenuated DNMT1 binding to the activator protein-1 transcription factor present in the 15-PGDH promoter region. A nonelectrophilic analogue 9,10-dihydro-15d-PGJ failed to suppress the methylation of CpG islands present in 15-PGDH promoter and did not affect both DNMT1 activity and 15-PGDH expression. These findings suggest that the α,β-unsaturated carbonyl group present in 15d-PGJ is essential for its inactivation on DNMT1 and expression of 15-PGDH. In conclusion, 15d-PGJ plays as a hypomethylating agent through direct interaction with DNMT1 and consequently suppresses DNMT1-mediated hypermethylation of 15-PGDH promoter, leading to up-regulation of 15-PGDH expression.
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http://dx.doi.org/10.1080/10715762.2019.1576867DOI Listing
March 2019

Evaluation of marginal discrepancy of pressable ceramic veneer fabricated using CAD/CAM system: Additive and subtractive manufacturing.

J Adv Prosthodont 2018 Oct 22;10(5):347-353. Epub 2018 Oct 22.

Department of Dental Laboratory Science and Engineering, College of Health Science, Korea University, Seoul, Republic of Korea.

Purpose: The purpose of this study was to evaluate the marginal discrepancy of heat-pressed ceramic veneers manufactured using a CAD/CAM system.

Materials And Methods: The ceramic veneers for the abutment of a maxillary left central incisor were designed using a CAD/CAM software program. Ten veneers using a micro-stereolithography apparatus (AM group), ten veneers using a five-axis milling machine (SM group), and ten veneers using a traditional free-hand wax technique (TW group) were prepared according to the respective manufacturing method. The ceramic veneers were also fabricated using a heat-press technique, and a silicone replica was used to measure their marginal discrepancy. The marginal discrepancies were measured using a digital microscope (×160 magnification). The data were analyzed using a nonparametric Kruskal-Wallis H test. Finally, post-hoc comparisons were conducted using Bonferroni-corrected Mann-Whitney U tests (α=.05).

Results: The mean±SD of the total marginal discrepancy was 99.68±28.01 µm for the AM group, 76.60±28.76 µm for the SM group, and 83.08±39.74 µm for the TW group. There were significant differences in the total marginal discrepancies of the ceramic veneers (<.05).

Conclusion: The SM group showed a better fit than the AM and TW groups. However, all values were within the clinical tolerance. Therefore, CAD/CAM manufacturing methods can replace the traditional free-hand wax technique.
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http://dx.doi.org/10.4047/jap.2018.10.5.347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202431PMC
October 2018

17β-Estradiol reduces inflammation and modulates antioxidant enzymes in colonic epithelial cells.

Korean J Intern Med 2020 03 22;35(2):310-319. Epub 2018 Oct 22.

Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, Korea.

Background/aims: Estrogen is known to have protective effect in colorectal cancer development. The aims of this study are to investigate whether estradiol treatment reduces inflammation in CCD841CoN, a female human colonic epithelial cell line and to uncover underlying mechanisms of estradiol effects.

Methods: 17β-Estradiol (E2) effect was measured by Western blot after inducing inf lammation of CCD841CoN by tumor necrosis factor α (TNF-α). Expression levels of estrogen receptor α (ERα) and β (ERβ), cyclooxygenase-2 (COX-2), nuclear factor-κB (NF-κB), heme oxygenase-1 (HO-1), and NAD(P)H-quinone oxidoreductase-1 (NQO-1) were also evaluated.

Results: E2 treatment induced expression of ERβ but did not increase that of ERα. E2 treatment for 48 hours significantly elevated the expression of anti-oxidant enzymes, HO-1 and NQO-1. TNF-α treatment significantly increased the level of activated NF-κB (p < 0.05), and this increase was significantly suppressed by treatment of 10 nM of E2 (p < 0.05). E2 treatment ameliorated TNF-α-induced COX-2 expression and decrease of HO-1 expression. 4-(2-phenyl-5,7-bis(trifluoromethyl) pyrazolo(1,5-a)pyrimidin-3-yl)phenol (PHTPP), antagonist of ERβ, removed the inhibitory effect of E2 in the TNF-α-induced COX-2 expression (p = 0.05).

Conclusion: Estrogen seems to inhibit inflammation in female human colonic epithelial cell lines, through down-regulation of NF-κB and COX-2 expression and induction of anti-oxidant enzymes such as HO-1 and NQO-1.
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http://dx.doi.org/10.3904/kjim.2018.098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061017PMC
March 2020

Effect of Estradiol in an Azoxymethane/Dextran Sulfate Sodium-Treated Mouse Model of Colorectal Cancer: Implication for Sex Difference in Colorectal Cancer Development.

Cancer Res Treat 2019 Apr 1;51(2):632-648. Epub 2018 Aug 1.

Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, Korea.

Purpose: This study demonstrates that estradiol downregulates inflammation and inhibits colorectal cancer (CRC) development in azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model.

Materials And Methods: AOM/DSS-treated male and female mice were sacrificed at weeks 2, 10, and 16, to assess estrogen effects on colitis and carcinogenesis. Macroscopic and histologic severity of colitis and Western blot and quantitative real-time polymerase chain reaction were evaluated, to measure inflammatory mediators and cytokines.

Results: Compared with AOM/DSS-treated male mice (M-AOM/DSS group), AOM/DSS-treated male mice with estradiol administration (M-AOM/DSS+estr group) displayed at week 2 significantly decreased severity of colitis. At weeks 10 and 16, AOM/DSS-treated female mice (F-AOM/DSS group) and the M-AOM/DSS+estr group showed significantly lower tumor multiplicity compared with the M-AOM/DSS group. At week 2, F-AOM/DSS group had a lower level of nuclear factor-κB (NF-κB) expression and higher level of nuclear factor erythroid 2-related factor 2 (Nrf2) expression, compared to the M-AOM/DSS group. At week 2, expression levels of NF-κB and its related mediators decreased in the M-AOM/DSS+estr group, while levels of Nrf2 and Nrf2-related anti-oxidant enzymes increased. In addition, estradiol significantly increased Nod-like receptor protein 3 (NLRP3) inflammasome expressions in AOM/DSS-treated male mice. In contrast, at weeks 10 and 16, Nrf2 and its-related anti-oxidant enzymes and NLRP3 inflammasome were highly expressed in M-AOM/DSS group and in F-AOM/DSS group, who developed cancer.

Conclusion: The data suggest that estradiol inhibits the initiation of CRC by regulating Nrf2-related pathways. Moreover, these imply the dual role of Nrf2 and NLRP3 inflammasome, including promotion of tumor progression upon tumor initiation.
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http://dx.doi.org/10.4143/crt.2018.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473282PMC
April 2019

In Vitro Osteogenic Differentiation and Antibacterial Potentials of Chalcone Derivatives.

Mol Pharm 2018 08 24;15(8):3197-3204. Epub 2018 Jul 24.

Department of Chemical and Biomolecular Engineering , Yonsei University , 50 Yonsei-ro , Seodaemun-gu, Seoul 03722 , Republic of Korea.

Chalcone derivatives have been investigated as therapeutic agents for the anticancer, antioxidant, and anti-inflammatory fields. In this study, we have synthesized four different types of chalcone derivatives and demonstrated in vitro bioactivities. We divided these derivatives into two groups of chalcones on the basis of similar substituents on the aromatic rings, and we tested cell viability and proliferation potentials, which indicated that the methoxy substituent on the A ring could enhance cytotoxicity and antiproliferation potential depending on the chalcone concentration. We also investigated osteogenic differentiation of C2C12 cells by ALP staining, the early marker for osteogenesis, which demonstrated that the chalcones could not only induce activity of BMP-2 but also inhibit the activity of noggin, a BMP antagonist. In addition, chalcone bearing hydroxyl groups at the 2-, 4-, and 6-position on the A ring inhibited treptococcus mutans growth, a major causative agent of dental caries. Therefore, we concluded that the chalcone derivatives synthesized in this research can be good candidates for therapeutic agents promoting bone differentiation, with an expectation of inhibiting S. mutans, in dentistry.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00288DOI Listing
August 2018

Diagnostic value of peripheral blood immune profiling in colorectal cancer.

Ann Surg Treat Res 2018 Jun 29;94(6):312-321. Epub 2018 May 29.

Immunology Laboratory, Seoul Song Do Colorectal Hospital, Seoul, Korea.

Purpose: Little is known about the clinical value of peripheral blood immune profiling. Here, we aimed to identify colorectal cancer (CRC)-related peripheral blood immune cells and develop liquid biopsy-based immune profiling models for CRC diagnosis.

Methods: Peripheral blood from 131 preoperative patients with CRC and 174 healthy controls was analyzed by flow cytometry and automated hematology. CRC-related immune factors were identified by comparing the mean values of immune cell percentages and counts. Subsequently, CRC diagnostic algorithms were constructed using binary logistic regression.

Results: Significant differences were observed in percentages and counts of white blood cells, lymphocytes, neutrophils, regulatory T cells, and myeloid-derived suppressor cells (MDSCs) of patients and controls. The neutrophil/lymphocyte and Th1/Th2 ratios were also significantly different. Likewise, the percentages and counts of peripheral blood programed death 1, cytotoxic T lymphocyte antigen 4, B-and T-lymphocyte attenuator, and lymphocyte activation gene-3 were higher in patients with CRC. The binary logistic regression model included 12 variables, age, CD3%, NK%, CD4CD279%, CD4CD25%, CD4CD152%, CD3CD366%, CD3CD272%, CD3CD223%, CD158bCD314CD3CD56%, Th2%, and MDSCs cells/µL, for the prediction of cancer. Results of retrospective and prospective evaluation of the area under the curve, sensitivity, and specificity were 0.980 and 0.940, 91.53% and 85.80%, and 93.50% and 86.20%, respectively.

Conclusion: Peripheral blood immune profiling may be valuable in evaluating the immunity of CRC patients. Our liquid biopsy-based immune diagnostic method and its algorithms may serve as a novel tool for CRC diagnosis. Future largescale studies are needed for better characterization of its diagnostic value and potential for clinical application.
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http://dx.doi.org/10.4174/astr.2018.94.6.312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976572PMC
June 2018

Myc-nick promotes efferocytosis through M2 macrophage polarization during resolution of inflammation.

FASEB J 2018 10 2;32(10):5312-5325. Epub 2018 May 2.

Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.

A key event required for effective resolution of inflammation is efferocytosis, which is defined as phagocytic removal of apoptotic cells mostly by macrophages acquiring an alternatively activated phenotype (M2). c-Myc has been reported to play a role in alternative activation of human macrophages and is proposed as one of the M2 macrophage markers. We found that M2-like peritoneal macrophages from zymosan A-treated mice exhibited a marked accumulation of Myc-nick, a truncated protein generated by a Calpain-mediated proteolytic cleavage of full-length c-Myc. Further, ectopic expression of Myc-nick in murine bone marrow-derived macrophages promoted the M2 polarization and, consequently, enhanced their efferocytic capability. Notably, Myc-nick-induced efferocytosis was found to be tightly associated with α-tubulin acetylation by K acetyltransferase 2a (Kat2a/Gcn5) activity. These findings suggest Myc-nick as a novel proresolving mediator that has a fundamental function in maintaining homeostasis under inflammatory conditions.-Zhong, X., Lee, H.-N., Kim, S. H., Park, S.-A., Kim, W., Cha, Y.-N., Surh, Y.-J. Myc-nick promotes efferocytosis through M2 macrophage polarization during resolution of inflammation.
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http://dx.doi.org/10.1096/fj.201800223RDOI Listing
October 2018

Roles of three FurA paralogs in the regulation of genes pertaining to peroxide defense in Mycobacterium smegmatis mc 155.

Mol Microbiol 2018 06 15;108(6):661-682. Epub 2018 Apr 15.

Department of Microbiology, Pusan National University, Busan, 46241, Korea.

Mycobacterium smegmatis mc 155 has three genes (MSMEG_6383, furA1; MSMEG_3460, furA2; MSMEG_6253, furA3) encoding FurA (ferric-uptake regulator A) paralogs. Three FurA paralogs in M. smegmatis are functionally redundant and negatively regulate expression of a subset of genes involved in peroxide detoxification such as ahpC, katG1 and katG2, as well as their own genes. The FurA paralogs sense H O via metal-catalyzed His oxidation (MCHO) in the same way as PerR. The propensity of FurA2 and FurA3 for MCHO is greater than that of FurA1. The three furA genes are transcribed into leaderless mRNAs lacking the Shine-Dalgarno (SD) sequence. FurA1 and FurA3 have the quaternary structure of homodimers like most Fur homologs, whereas FurA2 occurs as a monomer. The monomeric structure of FurA2 is determined by the C-terminal region of its dimerization domain. FurA2 monomers appear to cooperatively bind to the FurA-binding site with an inverted repeat configuration and have a broader binding specificity for the target DNA than dimeric FurA1 and FurA3. Comparative transcriptomic analysis revealed that the FurA paralogs do not regulate genes related to iron homeostasis in M. smegmatis, and that expression of SigF-regulated genes is significantly decreased in a furA triple mutant relative to the wild-type strain of M. smegmatis.
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http://dx.doi.org/10.1111/mmi.13956DOI Listing
June 2018

Liposome Preparation for the Analysis of Lipid-Receptor Interaction and Efferocytosis.

Curr Protoc Immunol 2018 02 21;120:14.44.1-14.44.21. Epub 2018 Feb 21.

Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland.

Efficient phagocytosis of apoptotic cells (efferocytosis) is essential for immune homeostasis. Phospholipids exposed on the surface of apoptotic cells, such as phosphatidylserine, supply important "eat-me" signals. Liposomes are lipid bilayer vesicles that can be generated from one or several types of phospholipids of interest. Thus, these vesicles offer versatility, flexibility, and, importantly, a three-dimensional structure for studying the interaction between lipids and their receptors as well as the lipid-receptor interaction-mediated signaling events controlling efferocytosis by cells like professional phagocytes. Here, we describe methods to prepare liposomes, perform liposome-based lipid-receptor binding assays, use liposomes to block efferocytosis, and utilize liposome-coated beads as apoptotic cell surrogates for phagocytosis. © 2018 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpim.43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844359PMC
February 2018

RvD1 inhibits TNFα-induced c-Myc expression in normal intestinal epithelial cells and destabilizes hyper-expressed c-Myc in colon cancer cells.

Biochem Biophys Res Commun 2018 02 3;496(2):316-323. Epub 2018 Jan 3.

Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address:

Inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, are persistent disorders that lead to development of colitis-associated cancer (CAC). Facilitated resolution of colitis has been addressed as a novel therapeutic strategy to control development of CAC. Resolvin D1 (RvD1) is an endogenous lipid mediator that is generated from docosahexaenoic acid during the resolution of inflammation. Although the pro-resolving effects of RvDs have been extensively investigated and well defined, the role for RvD1 in CAC remains largely unknown. In this study, we found that RvD1 inhibited the expression of c-Myc in normal colon cells stimulated with tumor necrosis factor-α (TNFα) and also in colon cancer cells. The suppression of TNFα-induced upregulation of c-Myc in normal cells was mediated through attenuation of NF-κB signaling. Notably, RvD1 destabilized the constitutively overexpressed c-Myc protein in HCT 116 human colon cancer cells by stimulating its ubiquitination and subsequent proteasomal degradation. Further, we revealed that RvD1 stimulated c-Myc degradation through direct interaction with the ALX/FPR2 receptor. This interaction resulted in inhibition of activation of extracellular signal-regulated kinase, thereby attenuating phosphorylation-dependent stabilization of c-Myc.
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http://dx.doi.org/10.1016/j.bbrc.2017.12.171DOI Listing
February 2018

Translation and Linguistic Validation of the Korean Version of the Treatment Satisfaction Visual Analogue Scale and the Overactive Bladder Satisfaction With Treatment Questionnaire.

Int Neurourol J 2017 Dec 31;21(4):309-319. Epub 2017 Dec 31.

Department of Urology, Seoul Metropolitan Government - Seoul National University Boramae Medical Center, Seoul, Korea.

Purpose: This study reports the development of the Korean Version of the Treatment Satisfaction Visual Analogue Scale (TS-VAS) and the Overactive Bladder Satisfaction with Treatment Questionnaire (OAB-SAT-q) based on the original versions, with subsequent linguistic validation by Korean patients with overactive bladder receiving active treatment from a physician.

Methods: Translation and linguistic validation were performed in 2016. The validation process included permission for translation, forward translation, reconciliation, backward translation, cognitive debriefing, and proofreading. The original versions of the TS-VAS and OAB-SAT-q were independently translated into Korean by 2 bilingual translators and were then reconciled into a single version. The third bilingual translator performed a backward translation of the reconciled version into English. A trained interviewer and 5 Korean-speaking patients with OAB carried out the cognitive debriefing.

Results: During the forward translation process, the terms used in the 2 questionnaires were adjusted to use more appropriate expressions in the Korean language than were used in the original versions. During the backward translation process, no changes were made in terms of semantic equivalence. In the cognitive debriefing session, 5 patients were asked to fill in the answers within 8 minutes; most of them reported that the translated questions were clear and easy to understand.

Conclusions: The present study presents successful linguistic validation of the Korean version of the TS-VAS and OAB-SAT-q, which could be useful tools for evaluating treatment satisfaction in patients.
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http://dx.doi.org/10.5213/inj.1734992.496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756819PMC
December 2017

Evaluation of marginal and internal gaps in single and three-unit metal frameworks made by micro-stereolithography.

J Adv Prosthodont 2017 Aug 16;9(4):239-243. Epub 2017 Aug 16.

Department of Dental Laboratory Science and Engineering, College of Health Science, Korea University, Seoul, Republic of Korea.

Purpose: The purpose of this study is to compare single and three-unit metal frameworks that are produced by micro-stereolithography.

Materials And Methods: Silicone impressions of a selected molar and a premolar were used to make master abutments that were scanned into a stereolithography file. The file was processed with computer aided design software to create single and three-unit designs from which resin frameworks were created using micro-stereolithography. These resin frameworks were subjected to investment, burnout, and casting to fabricate single and three-unit metal ones that were measured under a digital microscope by using the silicone replica technique. The measurements were verified by means of the Mann-Whitney U test (α=.05).

Results: The marginal gap was 101.9 ± 53.4 µm for SM group and 104.3 ± 62.9 µm for TUM group. The measurement of non-pontics in a single metal framework was 93.6 ± 43.9 µm, and that of non-pontics in a three-unit metal framework was 64.9 ± 46.5 µm. The dimension of pontics in a single metal framework was 110.2 ± 61.4 µm, and that of pontics in a three-unit metal framework was 143.7 ± 51.8 µm.

Conclusion: The marginal gap was smaller for the single metal framework than for the three-unit one, which requires further improvement before it can be used for clinical purposes.
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http://dx.doi.org/10.4047/jap.2017.9.4.239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582088PMC
August 2017

Inhibition of the DevSR Two-Component System by Overexpression of Mycobacterium tuberculosis PknB in Mycobacterium smegmatis.

Mol Cells 2017 Sep 25;40(9):632-642. Epub 2017 Aug 25.

Department of Microbiology, Pusan National University, Busan 46241, Korea.

The DevSR (DosSR) two-component system, which is a major regulatory system involved in oxygen sensing in mycobacteria, plays an important role in hypoxic induction of many genes in mycobacteria. We demonstrated that overexpression of the kinase domain of Mycobacterium tuberculosis (Mtb) PknB inhibited transcriptional activity of the DevR response regulator in Mycobacterium smegmatis and that this inhibitory effect was exerted through phosphorylation of DevR on Thr180 within its DNA-binding domain. Moreover, the purified kinase domain of Mtb PknB significantly phosphorylated RegX3, NarL, KdpE, TrcR, DosR, and MtrA response regulators of Mtb that contain the Thr residues corresponding to Thr180 of DevR in their DNA-binding domains, implying that transcriptional activities of these response regulators might also be inhibited when the kinase domain of PknB is overexpressed.
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http://dx.doi.org/10.14348/molcells.2017.0076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638771PMC
September 2017

Dendritic cells expressing immunoreceptor CD300f are critical for controlling chronic gut inflammation.

J Clin Invest 2017 May 17;127(5):1905-1917. Epub 2017 Apr 17.

Proinflammatory cytokine overproduction and excessive cell death, coupled with impaired clearance of apoptotic cells, have been implicated as causes of failure to resolve gut inflammation in inflammatory bowel diseases. Here we have found that dendritic cells expressing the apoptotic cell-recognizing receptor CD300f play a crucial role in regulating gut inflammatory responses in a murine model of colonic inflammation. CD300f-deficient mice failed to resolve dextran sulfate sodium-induced colonic inflammation as a result of defects in dendritic cell function that were associated with abnormal accumulation of apoptotic cells in the gut. CD300f-deficient dendritic cells displayed hyperactive phagocytosis of apoptotic cells, which stimulated excessive TNF-α secretion predominantly from dendritic cells. This, in turn, induced secondary IFN-γ overproduction by colonic T cells, leading to prolonged gut inflammation. Our data highlight a previously unappreciated role for dendritic cells in controlling gut homeostasis and show that CD300f-dependent regulation of apoptotic cell uptake is essential for suppressing overactive dendritic cell-mediated inflammatory responses, thereby controlling the development of chronic gut inflammation.
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http://dx.doi.org/10.1172/JCI89531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409274PMC
May 2017

15-Deoxy-Δ-Prostaglandin J Exerts Proresolving Effects Through Nuclear Factor E2-Related Factor 2-Induced Expression of CD36 and Heme Oxygenase-1.

Antioxid Redox Signal 2017 Dec 12;27(17):1412-1431. Epub 2017 May 12.

1 Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.

Aims: 15-Deoxy-Δ-prostaglandin J (15d-PGJ) has been shown to rescue cells from inflammatory insults and to participate in the resolution of acute inflammation. In this study, we investigated molecular mechanisms underlying proresolving effects of 15d-PGJ.

Results: 15d-PGJ injected into the peritoneum of mice facilitated the resolution of zymosan A-induced peritonitis. 15d-PGJ administration reduced the number of total leukocytes and attenuated polymorphonuclear leukocyte infiltration. Furthermore, 15d-PGJ increased the proportion of macrophages engulfing apoptotic neutrophils, a process called efferocytosis. In addition, when the thioglycollate-elicited mouse peritoneal macrophages were stimulated with 15d-PGJ, their efferocytic activity was amplified. In another experiment, RAW264.7 murine macrophages exposed to 15d-PGJ conducted phagocytic clearance of apoptotic cells to a greater extent than the control cells. Under these conditions, expression of CD36 and heme oxygenase-1 (HO-1) was enhanced along with increased accumulation of the nuclear factor E2-related factor 2 (Nrf2) in the nucleus. Knockdown of Nrf2 abolished 15d-PGJ-induced expression of CD36 and HO-1, and silencing of CD36 and HO-1 attenuated 15d-PGJ-induced efferocytosis. Moreover, peritoneal macrophages isolated from Nrf2-null mice failed to upregulate 15d-PGJ-induced expression of CD36 and HO-1 and to mediate efferocytosis. Unlike 15d-PGJ, its nonelectrophilic analog 9,10-dihydro-15d-PGJ lacking the α,β-unsaturated carbonyl group could not induce CD36 expression and efferocytosis.

Innovation: 15d-PGJ, as one of the terminal products of cyclooxygenase-2, exerts proresolving effects through induction of efferocytosis. The results of this study suggest that 15d-PGJ possesses a therapeutic value in the management of inflammatory disorders.

Conclusion: 15d-PGJ facilitates resolution of inflammation by inducing Nrf2-induced expression of CD36 and HO-1 in macrophages. Antioxid. Redox Signal. 27, 1412-1431.
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http://dx.doi.org/10.1089/ars.2016.6754DOI Listing
December 2017

Change of Ultrasound Estimated Bladder Weight and Bladder Wall Thickness After Treatment of Bladder Outlet Obstruction With Dutasteride.

Low Urin Tract Symptoms 2017 May 27;9(2):67-74. Epub 2015 Jul 27.

Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Objectives: To investigate the change of bladder wall hypertrophy to relieve bladder outlet obstruction (BOO) by treatment with 5α-reductase inhibitor.

Methods: Men who have BOO confirmed by urodynamic study (BOO index ≥40) were treated with dutasteride 0.5 mg once a day for 6 months. We measured ultrasound estimated bladder weight (UEBW), UEBW divided by body surface area (UEBW/BSA), and bladder wall thickness (BWT) before and after treatment. Changes in LUTS parameters were assessed by using the International Prostate Symptom Score, uroflowmetry, residual urine volume, prostate volume, serum prostate-specific antigen (PSA), and LUTS outcome scores (LOS). Correlation between the change of LUTS parameters and UEBW, UEBW/BSA, and BWT were evaluated. We assessed the changes of bladder wall hypertrophy according to the results of benefit, satisfaction, and willingness to continue (BSW) questionnaire.

Results: Thirty patients completed the 6-month study. The mean UEBW was 47.10 ± 7.79 g before and 50.07 ± 5.39 g after dutasteride treatment (P = 0.259). The mean UEBW/BSA was 26.47 ± 4.30 g/m before and 28.2 ± 3.53 g/m after treatment (P = 0.253), and there was no definite change in mean BWT after treatment (P = 0.301). Most LUTS parameters including LOS significantly improved. Increased BOO index value was related to decreased BWT (ρ = 0.361, P = 0.049). There was no definite change in mean UEBW, UEBW/BSA, and BWT according to the results of the BSW questionnaire.

Conclusions: There was no change in UEBW, UEBW/BSA and BWT despite improving most clinical parameters suggesting BOO. The changes of bladder wall hypertrophy parameters still have limitations to directly reflect the relief of BOO.
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http://dx.doi.org/10.1111/luts.12110DOI Listing
May 2017

The Effect of Sex on the Azoxymethane/Dextran Sulfate Sodium-treated Mice Model of Colon Cancer.

J Cancer Prev 2016 Dec 30;21(4):271-278. Epub 2016 Dec 30.

Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.

Background: The colitis-associated cancer exhibits different characteristics according to sex in the initiation and progression of the tumors. The aim of this study was to investigate the sex-associated difference in the azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated cancer model.

Methods: The AOM/DSS ICR mouse model was established to compare male with female, and then the severity of colitis-associated carcinogenesis was examined macroscopically and histologically regarding the number, size, and location of tumors. Subsequently, levels of colonic mucosal cytokine, interleukin (IL)-1β and myeloperoxidase (MPO) were assessed.

Results: At the 16th week, the tumor multiplicity and the pro-inflammatory factors differed according to sex. The total tumor number was significantly higher in male ( = 0.020) and the number of large tumors (diameter > 2 mm) was higher in male ( = 0.026). In male, the tumors located more in distal colon ( = 0.001). MPO was significantly higher in AOM/DSS-treated male mice compared to the control group ( = 0.003), whereas the corresponding female group showed no significant change ( = 0.086). Colonic IL-1β level significantly increased in AOM/DSS groups compared to control groups both in male and female (male, = 0.014; female, = 0.005). It was higher in male group; however, there was no statistical significance ( = 0.226).

Conclusions: In AOM/DSS murine model, colitis-associated colon tumorigenesis are induced more severely in male mice than female probably by way of inflammatory mediators such as IL-1β and MPO. The sex-related differences at the animal model of colon cancer suggest the importance of approach to disease with sex-specific medicine in human.
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http://dx.doi.org/10.15430/JCP.2016.21.4.271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207612PMC
December 2016