Publications by authors named "Young Sik Choi"

106 Publications

High mobility group box-1 promotes inflammation in endometriotic stromal cells through Toll-like receptor 4/nuclear factor-kappa B.

Am J Transl Res 2021 15;13(3):1400-1410. Epub 2021 Mar 15.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine Seoul, Republic of Korea.

Objective: To investigate whether high-mobility group box-1 induces cell proliferation, invasion and mediates inflammation in ectopic human endometrial stromal cells through Toll-like receptor 4.

Methods: Ectopic endometrial specimens were retrieved from patients with ovarian endometrioma having laparoscopy. Ectopic HESCs were treated with HO and recombinant HMGB-1 to induce oxidative stress. The effect of oxidative stress on cell proliferation and invasion was demonstrated. Receptors for HMGB-1 in NF-κB pathway (TLR4, RAGE), angiogenic molecule (VEGF), adhesion molecules (ICAM-1, E-cadherin), and inflammatory cytokines were measured simultaneously to the oxidative stress.

Results: Ectopic HESCs showed markedly decreased cell viability with the increased release of HMGB-1 following treatment with HO. When ectopic HESCs were stressed by rHMGB-1, cell proliferation and cell migration numbers increased significantly in a dose-dependent manner. Increased TLR4 and RAGE mRNA and protein expression levels were noted to rHMGB-1 treatment in a dose-dependent manner. VEGF synthesis was also increased by rHMGB-1 treatment. The gene expression of ICAM-1 was upregulated, whereas that of E-cadherin was downregulated with rHMGB-1 treatment. Interleukin-6, IL-1β, tumor necrosis factor-alpha, and IL-10 were increased significantly by rHMGB-1 treatment. Inversely, after transfection of small interfering RNA against TLR4, rHMGB treatment resulted in decreased cell proliferation and invasion.

Conclusion: HMGB-1 activates the NF-κB pathway via TLR4 to increase cell proliferation, invasion, and the production of various inflammatory markers in HESCs. Thus, HMGB-1, TLR4, and NF-κB may represent potential therapeutic targets for the treatment of endometriosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014341PMC
March 2021

Non-alcoholic fatty liver disease in polycystic ovary syndrome women.

Sci Rep 2021 Mar 29;11(1):7085. Epub 2021 Mar 29.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

To evaluate risk factors leading to non-alcoholic fatty liver disease (NAFLD) occurrence in polycystic ovarian syndrome (PCOS) women. A retrospective cohort study of a total of 586 women diagnosed with PCOS aged 13-35 years at the gynecology department at a university hospital was done to evaluate PCOS phenotype, metabolic syndrome (MetS) diagnosis, body composition, insulin sensitivity, sex hormones, lipid profile, liver function, and transient elastography (TE). In PCOS women with NAFLD compared to those without, MetS diagnosis (Hazard ratio [HR] 5.6, 95% Confidence interval [CI] 2.2-14.4, p < 0.01) and hyperandrogenism (HA) (HR 4.4, 95% CI 1.4-13.4, p = 0.01) were risk factors significantly associated with subsequent NAFLD occurrence, whereas 2-h insulin level in 75 g glucose tolerance test (GTT) (HR 1.2, 95% CI 0.5-2.5, p = 0.70) and body mass index (BMI) > 25 kg/m (HR 2.2, 95% CI 0.6-8.0, p = 0.24) was not. Among NAFLD patients who underwent TE, a higher number of MetS components indicated a worse degree of fibrosis and steatosis. MetS diagnosis and HA at PCOS diagnosis were risk factors associated with NAFLD, while 2-h insulin level in 75 g GTT and obesity were not. Although elevated aspartate aminotransferase levels were significant for NAFLD risk, liver enzyme elevations may not be present until late liver damage. Further prospective studies of PCOS women with MetS or HA are warranted to determine whether patients without liver enzyme elevations should undergo preemptive liver examinations.
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http://dx.doi.org/10.1038/s41598-021-86697-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007604PMC
March 2021

Correction to: Aberrant Expression of Sodium-Potassium-Chloride Cotransporter in Endometriosis.

Reprod Sci 2021 Mar 24. Epub 2021 Mar 24.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.

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http://dx.doi.org/10.1007/s43032-021-00551-0DOI Listing
March 2021

Aberrant Expression of Sodium-Potassium-Chloride Cotransporter in Endometriosis.

Reprod Sci 2021 Mar 11. Epub 2021 Mar 11.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.

Cell membrane ion channels have important roles in cell migration during cancer development and metastasis. Although endometriosis is a benign gynecological disease, some migration and invasion characteristics of endometriosis are similar to those of cancer. However, only a few studies have examined cell membrane ion channels and their associations with endometriosis. This study aimed to investigate the effects of these ion channels on development of endometriosis. A total of 39 women who underwent laparoscopic ovarian cyst enucleation were included in the study population. Eutopic endometrium or ectopic endometrium tissues were obtained from each patient based on allocation to an endometriosis group (n=21) or a control group (n=18). Quantitative real-time PCR (qRT-PCR) and western blot analyses were performed to quantify NKCC1, NKCC2, and CLCN3 mRNA expression and protein concentrations. SiRNA transfection and migration assays of the endometrial stromal cells were performed to test the effects of the ion channels on the migration ability. The qRT-PCR and western blot analyses revealed significantly elevated mRNA expression and protein expression of NKCC1, NKCC2, and CLCN3 in the ectopic endometrial tissue from the patients with endometriosis (p < 0.05). Migration assay of siRNA transfected cells suggested a decreased migratory potential of the endometrial stromal cells (p < 0.001). The magnitudes of expression of NKCC1, NKCC2, and CLCN3 were positively correlated with endometrioma size. The increased expression of NKCC1, NKCC2, and CLCN3 in endometriosis offers opportunities to understand mechanisms of endometriosis and develop novel therapeutic approaches.
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http://dx.doi.org/10.1007/s43032-021-00531-4DOI Listing
March 2021

The role of gonadotropin-releasing hormone agonists in female fertility preservation.

Clin Exp Reprod Med 2021 Mar 18;48(1):11-26. Epub 2021 Feb 18.

Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.

Advances in anticancer treatments have resulted in increasing survival rates among cancer patients. Accordingly, the quality of life after treatment, particularly the preservation of fertility, has gradually emerged as an essential consideration. Cryopreservation of embryos or unfertilized oocytes has been considered as the standard method of fertility preservation among young women facing gonadotoxic chemotherapy. Other methods, including ovarian suppression and ovarian tissue cryopreservation, have been considered experimental. Recent large-scale randomized controlled trials have demonstrated that temporary ovarian suppression using gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy is beneficial for preventing chemotherapy-induced premature ovarian insufficiency in breast cancer patients. It should also be emphasized that GnRHa use during chemotherapy does not replace established fertility preservation methods. All young women facing gonadotoxic chemotherapy should be counseled about and offered various options for fertility preservation, including both GnRHa use and cryopreservation of embryos, oocytes, and/or ovarian tissue.
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http://dx.doi.org/10.5653/cerm.2020.04049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943347PMC
March 2021

Optimized culture system to maximize ovarian cell growth and functionality in vitro.

Cell Tissue Res 2021 Feb 13. Epub 2021 Feb 13.

Wake Forest Institute for Regernative Medicine, Wake Forest School of Medicine, Medical Center Boulvard, Winston Salem, NC, 27157, USA.

Ovaries are the primary physiological source of female sex hormones, which play a crucial role in maintaining ovarian cycle, determining secondary sexual characteristics and preparing the endometrium for implantation. In vitro follicle engineering has been used to investigate follicle development, including ovarian hormone production and gamete maturation. To engineer functional follicles, culture and expansion of the primary ovarian cells are essential. However, the phenotypic and functional characteristics of primary ovarian cells are often lost during culture. The objective of this study is to develop an optimized culture system for maintaining ovarian cell growth and functionality. Granulosa cells (GCs) and theca cells (TCs) were isolated from female rats. The addition of follicle-stimulating hormone (FSH) or luteinizing hormone (LH) to the basal culture media significantly enhanced the secretion of estradiol from GCs and androstenedione from TCs. Serum concentrations of 5% and 10% had a similar role in promoting ovarian cell expansion and secretion of estradiol and androstenedione hormones from both types of cells. Growth differentiation factor 9 (GDF9), bone morphogenic protein 15 (BMP15), BMP7 and basic fibroblast growth factor (bFGF) enhanced GC proliferation and estradiol production, respectively. Among them, the effect of bFGF was most significant. bFGF also enhanced TC proliferation. When GCs and TCs were cultured in 5% serum, gonadotropin and bFGF-containing medium, they proliferated exponentially throughout the culture period of up to 40 days while maintaining their functional characteristics. Taken together, these results indicate that our medium formula is optimal for maximizing proliferation of functionally differentiated ovarian cells.
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http://dx.doi.org/10.1007/s00441-021-03415-wDOI Listing
February 2021

Engineering Functional Rat Ovarian Spheroids Using Granulosa and Theca Cells.

Reprod Sci 2021 Jan 28. Epub 2021 Jan 28.

Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27101, USA.

Although menopausal hormone therapy (MHT) is the most effective approach to managing the loss of ovarian activity, serious side effects have been reported. Cell-based therapy is a promising alternative for MHT. This study constructed engineered ovarian cell spheroids and investigated their endocrine function. Theca and granulosa cells were isolated from ovaries of 10-week-old rats. Two types of engineered ovarian cell spheroids were fabricated through forced aggregation in microwells, multilayered spheroids with centralized granulosa aggregates surrounded by an outer layer of theca cells and mixed ovarian spheroids lacking spatial rearrangement. The ovarian cell spheroids were encapsulated into a collagen gel. Non-aggregated ovarian cells served as controls. The endocrine function of the engineered ovarian spheroids was assessed over 30 days. The structure of the spheroids was well maintained during culture. The secretion of 17β-estradiol from both types of engineered ovarian cell spheroids was higher than in the control group and increased continuously in a time-dependent manner. Secretion of 17β-estradiol in the multi-layered ovarian cell spheroids was higher than in the non-layered constructs. Increased secretion of progesterone was detected in the multi-layered ovarian cell spheroids at day 5 of culture and was sustained during the culture period. The initial secretion level of progesterone in the non-layered ovarian cell spheroids was similar to those from the controls and increased significantly from days 21 to 30. An in vitro rat model of engineered ovarian cell spheroids was developed that was capable of secreting sex steroid hormones, indicating that the hormone secreting function of ovaries can be recapitulated ex vivo and potentially adapted for MHT.
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http://dx.doi.org/10.1007/s43032-020-00445-7DOI Listing
January 2021

A prospective cohort study on effects of gemigliptin on cardiovascular outcomes in patients with type 2 diabetes (OPTIMUS study).

Sci Rep 2020 11 4;10(1):19033. Epub 2020 Nov 4.

Department of Internal Medicine, and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.

This study was performed to evaluate the long-term cardiovascular safety of gemigliptin in patients with type 2 diabetes mellitus (T2DM). After screening, eligible patients with T2DM were enrolled, received gemigliptin, and were followed up for a median of 2.50 years. The primary outcome was a composite of confirmed cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke (3-point major adverse cardiovascular event [MACE]). The key secondary outcomes were incidence of all-cause mortality and any other cardiovascular events. A total of 5179 patients were included in the study and 5113 were treated with gemigliptin. Overall, the primary outcome occurred in 26 patients within 12 months (estimated incidence by Cox proportional hazard model 0.49%, 95% CI 0.29-0.69%) and in 54 patients within 54 months (estimated incidence from Cox proportional hazard model 1.35%, 95% CI 0.92-1.77%). During the study period, the incidence rates of each component of the primary composite outcome were 0.04% (0.2 events per 1000 person-years) for cardiovascular death, 0.51% (2.2 events per 1000 person-years) for nonfatal myocardial infarction, and 0.61% (2.5 events per 1000 person-years) for nonfatal ischemic stroke. The incidence of all-cause mortality was 0.82% (3.2 events per 1000 person-years) and the incidences of other cardiovascular events were all less than 0.3%. In conclusion, T2DM patients who received gemigliptin exhibited a low incidence of the primary composite MACE and all-cause mortality. Therefore, the use of gemigliptin is expected to be safe without an increase in cardiovascular risk.Trial registration: The study was registered at ClinicalTrials.gov (identifier: NCT02290301).
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http://dx.doi.org/10.1038/s41598-020-75594-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642439PMC
November 2020

Effect of sex hormones on coronavirus disease 2019: an analysis of 5,061 laboratory-confirmed cases in South Korea.

Menopause 2020 12;27(12):1376-1381

Department of Internal Medicine, Division of Infectious Disease, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin-si, Republic of Korea.

Objective: To evaluate the effect of female sex hormones on the clinical outcomes of coronavirus disease 2019 patients using national claims data.

Methods: This retrospective cohort study used the Health Insurance Review and Assessment data of 5,061 adult patients with laboratory-confirmed coronavirus disease 2019 in South Korea from January 20 to April 8, 2020. To evaluate the effect of hormone therapy on clinical outcomes among women, subgroup analyses using age-matched case-control data were performed.

Results: Coronavirus disease 2019 was most prevalent in women in the 20-39 years age group (1,250 [44.14%]). Men were more likely to receive oxygen therapy (144 [6.46%] vs 131 [4.63%], P = 0.004), be admitted to the intensive care unit (60 [2.69%] vs 53 [1.87%], P = 0.049), and have a longer length of stay after admission to the intensive care unit (19.70 ± 11.80 vs 14.75 ± 9.23, P = 0.016). However, there was no significant difference in the mortality rate (men vs women: 42 [1.88%] vs 42 [1.48%], P = 0.267). In the multivariable Cox analysis, older age and underlying comorbidities, but not sex, were independent risk factors for mortality. Hormone therapy was not significantly associated with clinical outcomes.

Conclusions: This study, using nationwide data, suggests that female sex hormones are not associated with the morbidity and clinical outcomes of coronavirus disease 2019 in South Korea.
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http://dx.doi.org/10.1097/GME.0000000000001657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709921PMC
December 2020

Genomic and Transcriptomic Characteristics According to Size of Papillary Thyroid Microcarcinoma.

Cancers (Basel) 2020 May 25;12(5). Epub 2020 May 25.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea.

It is controversial as to whether papillary thyroid microcarcinoma (PTMC) has some genomic and transcriptomic characteristics that differentiate between an early-stage lesion that would eventually evolve into the larger papillary thyroid cancer (PTC), and an occult indolent cancer in itself. To investigate this, we comprehensively elucidated the genomic and transcriptomic landscapes of PTMCs of different sizes, using a large-scaled database. This study included 3435 PTCs, 1985 of which were PTMCs. We performed targeted next-generation sequencing for 221 PTCs and integrated these data with the data including The Cancer Genome Atlas (TCGA) project. The frequency of v-raf murine sarcoma viral oncogene homolog B () mutation was higher in PTMCs >0.5 cm than that in very small PTMCs (≤0.5 cm) and decreased again in PTCs >2 cm. Among PTMCs, the prevalence of mutations in rat sarcoma () and telomerase reverse transcriptase () promoter was not significantly different according to their size, but lower than in large PTCs. There was no change in the tumor mutational burden, the number of driver mutations, and transcriptomic profiles with tumor size, among PTMCs and all PTCs. Although a few genes with differential expression and promoter mutations were found in a few PTMCs, our findings showed that there were no useful genomic or transcriptomic characteristics for the prediction of the future progression of PTMC.
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http://dx.doi.org/10.3390/cancers12051345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281223PMC
May 2020

Hydrogel cross-linking-programmed release of nitric oxide regulates source-dependent angiogenic behaviors of human mesenchymal stem cell.

Sci Adv 2020 02 26;6(9):eaay5413. Epub 2020 Feb 26.

Department of Medical Engineering, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Angiogenesis is stimulated by nitric oxide (NO) production in endothelial cells (ECs). Although proangiogenic actions of human mesenchymal stem cells (hMSCs) have been extensively studied, the mechanistic role of NO in this action remains obscure. Here, we used a gelatin hydrogel that releases NO upon crosslinking by a transglutaminase reaction ("NO gel"). Then, the source-specific behaviors of bone marrow versus adipose tissue-derived hMSCs (BMSCs versus ADSCs) were monitored in the NO gels. NO inhibition resulted in significant decreases in their angiogenic activities. The NO gel induced pericyte-like characteristics in BMSCs in contrast to EC differentiation in ADSCs, as evidenced by tube stabilization versus tube formation, 3D colocalization versus 2D coformation with EC tube networks, pericyte-like wound healing versus EC-like vasculogenesis in gel plugs, and pericyte versus EC marker production. These results provide previously unidentified insights into the effects of NO in regulating hMSC source-specific angiogenic mechanisms and their therapeutic applications.
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http://dx.doi.org/10.1126/sciadv.aay5413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043909PMC
February 2020

Identification of Serum Biomarkers for Diagnosis of Endometriosis Using Multiplex Immunoassays.

Reprod Sci 2020 05 6;27(5):1139-1147. Epub 2020 Jan 6.

Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, South Korea.

Endometriosis is a common gynecologic disorder characterized by chronic pelvic pain, dysmenorrhea, and infertility. Although this condition places significant financial burden on the healthcare system and negatively affects patient's quality of life, the pathophysiology of the disease remains unclear, and noninvasive diagnostic methods are insufficient. The object of this study was to identify potential biomarkers for endometriosis from peripheral blood. We hypothesized that serum biomarkers modified in endometriosis patients would be detected by multiplex cytokine panel, and identification of a combination of these biomarkers would improve diagnostic power. A total of 141 women, aged 15-52 years with regular menstruation, participated in this study. Twenty-one serum cytokines were detected using the commercially available MILLIPLEX MAP Human Cytokine/Chemokine Kit Panel IV. Among these cytokines, breast- and kidney-expressed chemokine (BRAK)/chemokine (C-X-C motif) ligand 14 (CXCL14) was significantly decreased, and proliferation-inducing ligand (APRIL)/tumor necrosis factor ligand superfamily member 13 (TNFSF13) was significantly increased in endometriosis group. APRIL/TNFSF13 and BRAK/CXCL14 alone or in combination, however, failed to show adequate sensitivity or specificity for the diagnosis of endometriosis. Combination of APRIL/TNFSF13 and BRAK/CXCL14 with serum CA-125 levels yielded significantly higher sensitivity (71.2%) for detecting endometriosis without compromising specificity (80.8%) than CA-125 alone in a logistic regression model (P = 0.050). In conclusion, we identified a biomarker combination that detects endometriosis better than CA125 alone. Therefore, we conclude that multiplex cytokine panel is an efficient method for detecting endometriosis, and analysis of additional cytokine panels may lead to identification of a novel biomarker combination with superior diagnostic power.
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http://dx.doi.org/10.1007/s43032-019-00124-2DOI Listing
May 2020

Operative hysteroscopy-assisted pregnancy termination after failed surgical abortion in missed abortion of woman with complete septate uterus.

Obstet Gynecol Sci 2020 Jan 26;63(1):102-106. Epub 2019 Dec 26.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

First trimester surgical abortion is an effective and safe procedure. Although its failure is uncommon, congenital uterine anomaly may be considered as one of the etiologic factors in such cases. Here, we report a rare case of surgical abortion failure that was successfully managed by operative hysteroscopy-assisted dilatation and evacuation (D&E) under ultrasound guidance in a woman with complete uterine septum. The patient was referred to Severance Hospital after two consecutive surgical abortion failures even under ultrasound guidance. A missed abortion in a left-sided hemicavity of septate uterus was noted on ultrasonography. Ultrasound-guided D&E was unsuccessful because the curette could not reach the uterine cavity with the gestational sac. Operative hysteroscopy revealed insufficient communication with the left-sided cavity just above the cervical internal os of the uterine septum. After widening the communication, ultrasound-guided D&E was successfully performed.
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http://dx.doi.org/10.5468/ogs.2020.63.1.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962582PMC
January 2020

Polycystic ovarian morphology is associated with primary dysmenorrhea in young Korean women.

Obstet Gynecol Sci 2019 Sep 22;62(5):329-334. Epub 2019 Jul 22.

Department of Obstetrics and Gynecology, Severance Hospital, CHA University School of Medicine, Seoul, Korea.

Objective: This study was aimed at identifying a correlation between polycystic ovarian morphology (PCOM) and the severity of primary dysmenorrhea in young Korean women.

Methods: A total of 592 patients who visited a tertiary hospital from March 2008 to March 2015 for dysmenorrhea were examined. After excluding those with secondary causes of menstrual pain (for example, myoma, adenomyosis, endometriosis, and pelvic inflammatory disease), 361 women were recruited and retrospectively analyzed. Severe dysmenorrhea was defined as a visual analog scale (VAS) score ≥6.

Results: The mean patient age was 23.0±4.0 years, the average menstrual cycle length was 34.4±23.7 days, and the average pain intensity was VAS 6.7±0.1 at baseline. PCOM was assessed by ultrasound in 54 women (15%). Patients with severe menstrual pain were more likely to have irregular menstrual cycles (=0.03) and heavy menstrual flow (=0.01) than those with mild menstrual pain. After adjusting for weight, height, menstrual cycle interval, and menstrual flow in the logistic regression analysis, PCOM (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.05-4.97; =0.04) and heavy menstrual flow (OR, 1.85; 95% CI, 1.05-3.28; =0.04) were found to be significant independent factors influencing pain.

Conclusion: Our study shows that PCOM may have a correlation with the severity of primary dysmenorrhea. Since PCOM may play a role in the development of menstrual pain, patients with PCOM should be under active surveillance with resources for prompt pain management readily available. It may also be necessary to further investigate the molecular mechanisms of pain development in primary dysmenorrhea.
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http://dx.doi.org/10.5468/ogs.2019.62.5.329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737062PMC
September 2019

Efficacy and Safety of Pioglitazone versus Glimepiride after Metformin and Alogliptin Combination Therapy: A Randomized, Open-Label, Multicenter, Parallel-Controlled Study.

Diabetes Metab J 2020 02 11;44(1):67-77. Epub 2019 Jul 11.

Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.

Background: There is limited information regarding the optimal third-line therapy for managing type 2 diabetes mellitus (T2DM) that is inadequately controlled using dual combination therapy. This study assessed the efficacy and safety of pioglitazone or glimepiride when added to metformin plus alogliptin treatment for T2DM.

Methods: This multicenter, randomized, active-controlled trial (ClinicalTrials.gov: NCT02426294) recruited 135 Korean patients with T2DM that was inadequately controlled using metformin plus alogliptin. The patients were then randomized to also receive pioglitazone (15 mg/day) or glimepiride (2 mg/day) for a 26-week period, with dose titration was permitted based on the investigator's judgement.

Results: Glycosylated hemoglobin levels exhibited similar significant decreases in both groups during the treatment period (pioglitazone: -0.81%, <0.001; glimepiride: -1.05%, <0.001). However, the pioglitazone-treated group exhibited significantly higher high density lipoprotein cholesterol levels (<0.001) and significantly lower homeostatic model assessment of insulin resistance values (<0.001). Relative to pioglitazone, adding glimepiride to metformin plus alogliptin markedly increased the risk of hypoglycemia (pioglitazone: 1/69 cases [1.45%], glimepiride: 14/66 cases [21.21%]; <0.001).

Conclusion: Among patients with T2DM inadequately controlled using metformin plus alogliptin, the addition of pioglitazone provided comparable glycemic control and various benefits (improvements in lipid profiles, insulin resistance, and hypoglycemia risk) relative to the addition of glimepiride.
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http://dx.doi.org/10.4093/dmj.2018.0274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043969PMC
February 2020

Role of B-Cell Translocation Gene 1 in the Pathogenesis of Endometriosis.

Int J Mol Sci 2019 Jul 9;20(13). Epub 2019 Jul 9.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea.

Estrogen affects endometrial cellular proliferation by regulating the expression of the gene. B-cell translocation gene 1 (BTG1), a translocation partner of the , is a tumor suppressor gene that promotes apoptosis and negatively regulates cellular proliferation and cell-to-cell adhesion. The aim of this study was to determine the role of BTG1 in the pathogenesis of endometriosis. mRNA and protein expression was evaluated in eutopic and ectopic endometrium of 30 patients with endometriosis (endometriosis group), and in eutopic endometrium of 22 patients without endometriosis (control group). The effect of BTG1 downregulation on cellular migration, proliferation, and apoptosis was evaluated using transfection of primarily cultured human endometrial stromal cells (HESCs) with siRNA. mRNA expression level of eutopic and ectopic endometrium of endometriosis group were significantly lower than that of the eutopic endometrium of the control group. Migration and wound healing assays revealed that BTG1 downregulation resulted in a significant increase in migration potential of HESCs, characterized by increased expression of matrix metalloproteinase 2 (MMP2) and MMP9. Downregulation of BTG1 in HESCs significantly reduced Caspase 3 expression, indicating a decrease in apoptotic potential. In conclusion, our data suggest that downregulation of BTG1 plays an important role in the pathogenesis of endometriosis.
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http://dx.doi.org/10.3390/ijms20133372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651142PMC
July 2019

MiR-150-5p May Contribute to Pathogenesis of Human Leiomyoma via Regulation of the Akt/p27 Pathway In Vitro.

Int J Mol Sci 2019 May 31;20(11). Epub 2019 May 31.

Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.

Uterine leiomyoma is found in ~50-80% of women of a reproductive age and is the most common reason for hysterectomy. Recently, posttranscriptional gene silencing by microRNAs (miRs) has been reported as a mechanism for regulating gene expression stability in the pathogenesis of uterine leiomyomas. In this study, miR microarray analysis of leiomyomas and paired myometrial tissue revealed numerous aberrantly expressed miRs, including miR-150. In functional assays, transfection with miR-150 mimic resulted in decreased migration and fibrosis, implying an inhibition of leiomyoma growth. To identify the target genes of miR-150 in leiomyoma, gene set analysis and network analysis were performed. To overcome the limitations of in silico analysis, changes in expression levels of hallmark genes in leiomyoma after transfection with a miR-150 mimic were also evaluated using qRT-PCR. As a result, the Akt/p27 pathway was presumed to be one of the target pathways of miR-150. After transfecting cultured leiomyoma cells with the miR-150 mimic, expression levels of its target gene Akt decreased, whereas those of p27 increased significantly. Our results suggest that miR-150 affects the cell cycle regulation in uterine leiomyoma through the Akt/p27 pathway.
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http://dx.doi.org/10.3390/ijms20112684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601023PMC
May 2019

Diagnosis of an indistinct Leydig cell tumor by positron emission tomography-computed tomography.

Obstet Gynecol Sci 2019 May 3;62(3):194-198. Epub 2019 May 3.

Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

A 51-year-old perimenopausal female patient presented with hirsutism and voice thickening which was started approximately one and a half years ago. Her initial hormone assay revealed elevated plasma testosterone, 5a-dihydrotestosterone, and dehydroepiandrosterone (DHEA) levels and therefore androgen-secreting tumor was first suspected. However, the lesion was inconspicuous on transvaginal sonography, abdominal-pelvic computed tomography (CT) scan, and pelvic magnetic resonance (MRI) imaging. Consequently, F-fluorodeoxyglucose (FDG) positron emission tomography-CT was performed, which localized the lesion as a focal FDG uptake within the right adnexa. Total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was performed, and although visible gross mass lesions were not observed intraoperatively, pure Leydig cell tumor was pathologically confirmed within the right ovary. Plasma testosterone, 5a-dihydrotestosterone, and DHEA levels were normalized postoperatively. Clinical signs of virilization were also significantly resolved after 3-months of follow-up.
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http://dx.doi.org/10.5468/ogs.2019.62.3.194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520550PMC
May 2019

Experiences of localization and removal of non-palpable subdermal contraceptive implants with ultrasound.

Obstet Gynecol Sci 2019 May 17;62(3):166-172. Epub 2019 Apr 17.

Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Objective: The aim of this study was to present experiences in localization and removal of non-palpable subdermal contraceptive implants with ultrasonography.

Methods: Medical records from January 1, 2016, to April 30, 2018, were retrospectively reviewed for 21 patients who were referred to a single institution and had an impalpable implant despite following the removal instruction. In all the cases, more than one attempt was made to remove the implant before referral. The rod was detected using radiography and ultrasonography. In all the cases, localization of the single implant was achieved with ultrasonography. The distal depth of the rod was measured, and skin marking was made following the echogenicity. The implants were subsequently removed under anesthesia.

Results: In 18 cases, the rods were localized using ultrasonography and successfully removed under local anesthesia. In the other three cases, removal with local anesthesia failed. Although the rod was detected successful with ultrasonography, the implants were removed under general anesthesia in the operating room. The depth from skin to rod, measured with ultrasonography, was >12.0 mm in all the cases and located deep in the muscular layer in the failure cases. The depth of the implants positively correlated with the time spent for removal (=0.525; =0.015).

Conclusion: High frequency ultrasonography is a highly accurate tool for localization and measurement of the skin-to-rod depth. It is also useful for removing non-palpable implants. If the depth of the implant is >12.0 mm, removal of the implant in the operating room under general anesthesia is recommended.
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http://dx.doi.org/10.5468/ogs.2019.62.3.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520546PMC
May 2019

Elevated serum interleukin-32 levels in patients with endometriosis: A cross-sectional study.

Am J Reprod Immunol 2019 08 11;82(2):e13149. Epub 2019 Jun 11.

Department of Obstetrics & Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

Problem: Recently, interleukin (IL)-32 has been suggested to be involved in the pathogenesis of endometriosis. The aim of this study was to investigate whether serum IL-32 level might be used as a biomarker for diagnosis of endometriosis.

Method Of Study: We recruited the serum samples of 50 patients with histologically confirmed endometriosis and 35 controls. Enzyme-linked immunosorbent assay was used to analyze the serum IL-32, IL-6, IL-10, tumour necrosis factor (TNF)-α, IL-1β, and CA-125 levels in patients with and without the disease and the diagnostic potentials of the cytokines were assessed using receiver operating characteristic curve and the area under the curve (AUC).

Results: Among evaluated cytokines, only serum IL-32 levels showed significant differences between patients with and without endometriosis (1111.24 ± 149.59 vs 631.10 ± 120.23 ng/mL, P = 0.018, respectively). When the diagnostic power of serum IL-32 was evaluated, the AUC was 0.638 (95% confidence interval (CI): 0.521-0.766, P = 0.031). When serum IL-32 levels were combined with serum CA-125 levels, the AUC was increased to 0.749 (95% CI: 0.640-0.858, P < 0.001) with sensitivity and specificity of 60.0% and 82.9% at cutoff value of 0.640, which led to detect 25 more cases of endometriosis than the use of serum CA 125 with the cutoff value of 35 IU/mL (36/50 vs 11/50, P < 0.001) without sacrificing the specificity of the marker.

Conclusion: Serum IL-32 levels are elevated in patients with endometriosis, and with combination of serum CA-125 levels, it may serve as a potential biomarker for endometriosis.
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http://dx.doi.org/10.1111/aji.13149DOI Listing
August 2019

Effect of deflazacort on pregnancy outcome in kidney transplant patients: should we change the immunosuppressant before conception?

BMC Nephrol 2019 05 14;20(1):161. Epub 2019 May 14.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Background: Despite the good prognosis in patients with transplant organs, limited evidence is available on how immunosuppressants affect pregnancy. The aim of this study was to determine whether immunosuppressant use affects the pregnancy outcome and to identify whether there is any need to change the immunosuppressant before the patient tries to conceive.

Methods: This retrospective cohort study included women with previous kidney transplantation history who visited the Department of Obstetrics and Gynecology for either infertility or antenatal care between January 2005 and May 2016. A total of 40 cases (36 women) met the inclusion criteria. Statistical analyses were performed using SAS version 9.4.

Results: There were no differences in the immunosuppressant regimen between the pregnant and non-pregnant groups (never-pregnant+miscarriage) (P = 0.73). Individual immunosuppressant use was significantly different in terms of pregnancy outcome among the never-pregnant, miscarriage, and clinical pregnancy groups (azathioprine, P = 0.01; deflazacort, P < 0.0001). Only deflazacort use differed significantly between the clinical pregnancy and non-pregnant groups (P = 0.003). After adjusting for factors that may affect pregnancy outcome, deflazacort use remained significantly associated with a decreased odds ratio for clinical pregnancy (P = 0.02). Cox regression analysis also showed that deflazacort use was the only remaining factor that could hinder the success of clinical pregnancy (P = 0.03).

Conclusions: Our study suggests that the type of immunosuppressive regimen may not affect the success of clinical pregnancy. However, deflazacort may decrease the possibility of clinical pregnancy in women with kidney transplant when they try to conceive.
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http://dx.doi.org/10.1186/s12882-019-1346-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515635PMC
May 2019

Potential roles of aquaporin 9 in the pathogenesis of endometriosis.

Mol Hum Reprod 2019 07;25(7):373-384

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.

Aquaporins (AQPs) are involved in cell migration, proliferation and carcinogenesis in tumor development and physiologic inflammatory processes, but their associations with endometriosis have not been fully evaluated. In this study, tissue samples were obtained from women undergoing laparoscopic surgery for endometriosis and other benign conditions. Analysis of expressions of AQP subtypes in eutopic and ectopic endometrium of patients with endometriosis (Eu-EMS and Ect-EMS, respectively) and eutopic endometrium of control patients without endometriosis (Eu-CTL) were performed using the NanoString nCounter System and western blotting. Human endometrial stromal cells (HESCs) were cultured and transfected with the siRNA of the AQP of interest. Among the AQP1-9 subtypes, endometrial expression of AQP2 and AQP8 was significantly increased, whereas AQP9 expression was significantly decreased in the Eu-EMS group compared to the Eu-CTL group. Comparison of expression of AQP2, AQP8 and AQP9 among Eu-EMS, Ect-EMS and Eu-CTL groups revealed significant differences for only AQP9. Expression of AQP9 in the Eu-EMS group was decreased compared with that in Eu-CTL. After transfection of AQP9 siRNA in HESCs, expressions of MMP2 and MMP9 were significantly elevated. Increased expression of phosphorylated ERK 1/2 and phosphorylated p38 MAPK proteins after transfection was also confirmed using western blot analysis. Increased migration and invasion potentials of HESCs after transfection were determined by migration and wound healing assays. These findings suggest that AQP9 may be involved in the pathogenesis of endometriosis and warrant further investigation as a potential therapeutic target for treating endometriosis.
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http://dx.doi.org/10.1093/molehr/gaz025DOI Listing
July 2019

Association Between Impairment of DNA Double Strand Break Repair and Decreased Ovarian Reserve in Patients With Endometriosis.

Front Endocrinol (Lausanne) 2018 21;9:772. Epub 2018 Dec 21.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.

Repair of DNA double strand break (DSB) is an important mechanism for maintaining genetic stability during a DNA damage event. Although, a growing body of recent evidence suggests that DNA DSBs and related repair mechanisms may be important in ovarian aging and in various cancers, there are few reports in endometriosis. We, therefore, examined expression levels of genes pertaining to DNA DSB repair in patients with endometriosis to assess the potential effects on ovarian reserves. A total of 69 women undergoing laparoscopic surgery for endometriosis and other benign conditions was included; endometriosis group ( = 38) vs. controls ( = 31). DNA DSBs in endometrial and ovarian tissues of both groups were compared via immunohistochemistry, aimed at γ-H2AX expression. To gauge genotoxin-induced DNA DSBs in endometrial stromal cells, γ-H2AX expression was determined by western blot after HO treatment of cultured endometrial stromal cells (endometriosis group and controls) and Ishikawa cell-line cultures. Endometrial and ovarian tissue levels of BRCA1, BRCA2, Rad51, and ATM (ataxia-telangiectasia mutated) mRNA expression were also compared. Correlations between expression levels of genes of interest and serum anti-müllerian hormone (AMH) levels were assessed as well. Expression of γ-H2AX in immunostained endometrial and ovarian tissue preparations was greater in the endometriosis group, compared with controls. After HO treatment, γ-H2AX expression levels were also significantly greater in cultured stromal cells of the endometriosis group and in the Ishikawa cell line than in controls. Endometrial expression of and mRNA proved significantly lower in the endometriosis group (vs. controls), as did ovarian expression of and mRNA. Serum AMH concentration showed a significant correlation with ovarian mRNA expression in women with endometriosis ( = 0.03). In women with endometriosis, expression levels of various genes implicated in DSB repair are decreased and ovarian expression correlates with.
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http://dx.doi.org/10.3389/fendo.2018.00772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308303PMC
December 2018

Comparison of congenital malformations among babies born after administration of letrozole or clomiphene citrate for infertility treatment in a Korean cohort.

Reprod Toxicol 2018 12 16;82:88-93. Epub 2018 Oct 16.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea; Institute of Women's Life Medical Science, Seodaemun-gu, Seoul, Republic of Korea. Electronic address:

This retrospective study investigated and compared the incidence of congenital foetal anomalies after letrozole versus clomiphene citrate (CC) administration for infertility treatment. Data from 142 newborns were included: letrozole group, n = 83; CC group, n = 61. Congenital anomalies were found in 7.2% (6/83) patients in the letrozole group and 18.0% (11/61) patients in the CC group, with no significant between-group difference (p = .066). Major congenital anomaly rate was 2.4% (2/83) in the letrozole group and 3.3% (2/61) in the CC group, with no significant between-group difference (p > 0.999). There was no significant difference in major and minor congenital anomalies between the groups after excluding premature infants (birth at a gestational age of <37 weeks), low birth weight, and very low birth weight. The results of this study demonstrate the stability of letrozole compared to that of CC for infertility treatment in pregnant women.
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http://dx.doi.org/10.1016/j.reprotox.2018.10.006DOI Listing
December 2018

Relationship between ultrasonographic and pathologic calcification patterns in papillary thyroid cancer.

Medicine (Baltimore) 2018 Oct;97(41):e12675

Department of Pathology, Kosin University College of Medicine, Busan, Korea.

Ultrasonographic microcalcification is highly related to papillary thyroid cancer (PTC) and pathologic psammoma body is a poor prognostic factor. However, it is little known about whether the microcalcifications seen on ultrasonography are consistent with the pathologic psammoma bodies. We evaluated the relationship between ultrasonographic (US) calcification types and pathologic calcification features, and the consistency between observed pathologic and US calcifications.US calcifications were classified into microcalcification (MC) and nonmicrocalcification (non-MC) types, and pathologic calcifications were classified into 3 types: psammoma bodies, stromal calcifications, and ossifications.Among the 411 nodules that were reviewed by a pathologist, 38.9% (n = 160) had any type of US calcification. The larger the size of pathologic calcification, the more calcification was present in US (psammoma 46.1% < stromal 53.7% < ossification 73.3%). Psammoma bodies occurred in all US MC type. Ossification nodules occurred in nearly all (92.3%) non-MC type. The stromal-only nodules were 36.8% MC-type and 63.2% non-MC type. MC-type had a significantly higher odds ratio than non-MC type for predicting psammoma bodies according to the logistic regression.The presence of MC in ultrasonography was consistent with the presence of psammoma bodies. This study suggests that US identification of MC may be a useful prognostic indicator of PTC aggressiveness.
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http://dx.doi.org/10.1097/MD.0000000000012675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203561PMC
October 2018

Use of the Endometriosis Fertility Index to Predict Natural Pregnancy after Endometriosis Surgery: A Single-Center Study.

Gynecol Obstet Invest 2019 20;84(1):86-93. Epub 2018 Sep 20.

Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.

Aims: Our objective was to predict natural pregnancy after endometriosis surgery using the endometriosis fertility index (EFI).

Methods: A retrospective medical records review was conducted, examining patients surgically treated for endometriosis at a single center in Korea between January 2009 and February 2015. In total, 68 women attempting natural conception were analyzed by assessing age, preoperative serum CA-125, body mass index, revised American Fertility Society (rAFS) stage, EFI, and pregnancy outcome. Kaplan-Meier estimates and log-rank tests were used to generate cumulative natural pregnancy rate curves based on an EFI cut-point. A receiver-operating characteristic (ROC) curve was plotted for EFI.

Results: Seventy-seven patients attempted conceptions, resulting in 33 natural and 9 assisted conceptions. Excluding assisted conceptions, the mean EFI scores of 68 women who were not pregnant and pregnant were 5.43 ± 0.36 and 6.88 ± 0.28 respectively. The relation between EFI and natural pregnancy was significant (cumulative overall pregnancy rate, p = 0.006), whereas rAFS stage was not (univariate logistics, p = 0.853). The cut-point for maximum natural pregnancy outcomes was 6 (area under ROC curve = 0.710, 95% CI 0.586-0.835).

Conclusion: The EFI is a reliable staging system for predicting natural pregnancy after endometriosis surgery. EFI scores can be used to guide postoperative treatment of women with endometriosis.
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http://dx.doi.org/10.1159/000493264DOI Listing
March 2019

A risk prediction model for medical treatment failure in tubal pregnancy.

Eur J Obstet Gynecol Reprod Biol 2018 Jun 20;225:148-154. Epub 2018 Apr 20.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Objective: Methotrexate is an alternative treatment for tubal pregnancy. However, despite initial treatment, ∼15% of women eventually require surgery. This study aimed to identify the risk factors for medical treatment failure in tubal pregnancy and apply them to a risk prediction model.

Study Design: This single-center retrospective cohort study included 123 participants initially treated medically for tubal pregnancy between January 2006 and December 2015. Logistic regression analysis was used to construct a risk prediction model (visually presented as a nomogram) for medical treatment failure. Model performance was assessed using discrimination and calibration. The medical treatment failure rate was 36.6%. The prediction model integrated the presence of a gestational sac, ectopic mass size, and follow-up β-human chorionic gonadotropin levels above cut-off values on days 4 and 7. The model used the following cut-off values: increased β-human chorionic gonadotropin levels by 1028.6 mIU/mL, 1.0457-fold higher than baseline level on day 4; and increased β-human chorionic gonadotropin levels by 1233 mIU/mL, 1.3025-fold higher than baseline level on day 7.

Results: The corresponding areas under the receiver-operating characteristic curves were 0.8135 (95% confidence interval, 0.733-0.893) for the day 4 model and 0.8600 for the day 7 model (95% confidence interval, 0.788-0.932). Comparison of the day 4 and 7 models revealed no significant difference in their predictive abilities (P = 0.4318).

Conclusions: This model identified a substantial proportion of the participants who experienced medical treatment failure for tubal pregnancy. It was visualized as a nomogram, facilitating clinical application.
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http://dx.doi.org/10.1016/j.ejogrb.2018.04.020DOI Listing
June 2018

Ginsenoside Rg3 Decreases Fibrotic and Invasive Nature of Endometriosis by Modulating miRNA-27b: In Vitro and In Vivo Studies.

Sci Rep 2017 12 15;7(1):17670. Epub 2017 Dec 15.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.

This research aimed to evaluate the potential therapeutic effects of Rg3 on endometriosis and identify target miRNAs. We designed an in vitro study using human endometrial stromal cells (HESCs) obtained from patients with endometriosis and an in vivo study using mouse models. HESCs were treated with Rg3-enhanced red ginseng extract (Rg3E); real-time PCR and microarray profiling, transfection, and western blot were performed. Mouse endometriosis models were developed and supplemented with Rg3E for 8 weeks. Gross lesion size and fibrotic character were analyzed in the mouse models. RNA levels of Ki-67, col-1, CTGF, fibronectin, TGF-β1, MMP2 and MMP9 significantly decreased in HESCs after Rg3E treatment. Microarray analysis revealed downregulation of miR-27b-3p, which is related to fibrosis modulation. Expression of miR-27b-3p was significantly higher in HESCs from patients with endometriosis than that of controls, and Rg3E treatment significantly decreased its expression; the contraction and migration assay revealed significant reductions in both fibrosis and migration potential in Rg3E-treated HESCs from endometriosis patients. A decrease in size and fibrotic character of endometrial lesions from the Rg3E groups was observed in vivo. In conclusion, Rg3 effectively altered fibrotic properties of HESCs from patients with endometriosis, which is likely associated with miR-27b-3p modulation.
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http://dx.doi.org/10.1038/s41598-017-17956-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732249PMC
December 2017

Trichostatin A Induces NAG-1 Expression and Apoptosis in Human Endometriotic Stromal Cells.

Reprod Sci 2018 09 20;25(9):1349-1356. Epub 2017 Nov 20.

1 Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.

To investigate the effects of trichostatin A (TSA) on nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1) expression and apoptosis in human endometriotic stromal cells (HESCs), ectopic endometrial tissues were obtained from 15 patients with endometriotic cysts who underwent cystectomy. Human endometriotic stromal cells were isolated and cultured with different concentrations of TSA. Nonsteroidal anti-inflammatory drug-activated gene-1 messenger RNA (mRNA) and protein levels were evaluated by real-time polymerase chain reaction and Western blotting, respectively, and apoptosis was assessed by flow cytometry. Viability of HESCs was reduced in a dose-dependent manner by treatment with TSA. The percentage of early and late apoptotic HESCs was increased upon treatment with TSA. Nonsteroidal anti-inflammatory drug-activated gene-1 mRNA and protein expression was induced in a dose-dependent manner by TSA treatment. Gene knockdown experiments using small-interfering RNA confirmed an association between NAG-1 expression and TSA-induced apoptosis. Whether effects of TSA on NAG-1 gene expression are enhanced in the presence of 5-aza-2'-deoxycytidine (5-aza-dC) are also investigated; however, TSA-induced apoptosis was unaffected by 5-aza-dC. In conclusion, TSA induced apoptosis in HESCs via induction of NAG-1 expression. These results suggest that upregulation of NAG-1 contributes to TSA-induced apoptosis in HESCs.
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http://dx.doi.org/10.1177/1933719117741372DOI Listing
September 2018