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Caffeic acid (CA) is produced from a variety of plants and has diverse biological functions, including anti-inflammation activity. It has been recently demonstrated that caffeoyl-prolyl-histidine amide (CA-PH), which is CA conjugated with proline-histidine dipeptide, relieves atopic dermatitis (AD)-like phenotypes in mouse. In this study, we investigated the molecular mechanism underlying CA-PH-mediated alleviation of AD-like phenotypes using cell line and AD mouse models. We confirmed that CA-PH suppresses AD-like phenotypes, such as increased epidermal thickening, infiltration of mast cells, and dysregulated gene expression of cytokines. CA-PH suppressed up-regulation of cytokine expression through inhibition of nuclear translocation of NF-&kappa, B. Using a CA-PH affinity pull-down assay, we found that CA-PH binds to Fyn. In silico molecular docking and enzyme kinetic studies revealed that CA-PH binds to the ATP binding site and inhibits Fyn competitively with ATP. CA-PH further suppressed spleen tyrosine kinase (SYK)/inhibitor of nuclear factor kappa B kinase (IKK)/inhibitor of nuclear factor kappa B (I&kappa, B) signaling, which is required for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-&kappa, B) activation. In addition, chronic application of CA-PH, in contrast with that of glucocorticoids, did not induce up-regulation of regulated in development and DNA damage response 1 (REDD1), reduction of mammalian target of rapamycin (mTOR) signaling, or skin atrophy. Thus, our study suggests that CA-PH treatment may help to reduce skin inflammation via down-regulation of NF-&kappa, B activation, and Fyn may be a new therapeutic target of inflammatory skin diseases, such as AD.

Purpose This study aimed to evaluate the prognostic value of each component of the revised American Fertility Society (rAFS) classification system for the first recurrence of endometriosis after conservative laparoscopy. Materials and methods As this was a retrospective cohort study, data were collected by reviewing medical records. A total of 379 women ages 18 to 49 years were included. Women who underwent conservative laparoscopy with histologic confirmation of endometriosis at Gangnam Severance Hospital between March 2003 and May 2010 were included. Individual components of the rAFS classification system as well as preoperative serum CA-125 levels were retrospectively analyzed to assess their prognostic values for recurrence of endometriosis. Results Of 379 patients, 80 (21.2%) were found to have recurrence of endometriosis. The median duration of follow-up was 19.0 months, and the mean age at the time of surgery was 31.8±6.7 years. In endometriosis of advanced stage, younger age at the time of surgery, bilateral ovarian cysts at the time of diagnosis, a rAFS ovarian adhesion score >24, and complete cul-de-sac obliteration were independent risk factors of poor outcomes, and a rAFS ovarian adhesion score >24 had the highest risk of recurrence [hazard ratio=2.948 (95% CI: 1.116-7.789), p=0.029]. Conclusion Our results suggest that of the rAFS adnexal adhesion scores, the ovarian adhesion score rather than the tubal adhesion score was associated with a significantly increased risk of recurrent endometriosis. The preoperative serum CA-125 level may be also a significant prognostic factor for recurrence, as known. However, it seemed to only have borderline significance in affecting recurrence in the current study.

Although a variety of factors have been reported as affecting pregnancy rates after intrauterine insemination (IUI), there have been conflicting results on prognostic factors. This study aimed to determine predictive factors for pregnancy in patients undergoing the first four IUI cycles.A total of 348 IUI cycles using clomiphene citrate or letrozole combined with gonadotropin, or gonadotropin only were analyzed. Baseline clinical characteristics, variables related to ovulation induction and sperm parameters were compared between pregnant (n = 54) and non-pregnant groups (n = 294). Logistic regression analysis was performed to identify factors that could predict a pregnancy.The overall clinical pregnancy rate was 15.5% (54/348) per cycle and 30.0% (54/180) per couple. During the first four IUI cycles, logistic regression analysis revealed that woman who were 39 years or older (OR: 0.263, 95% CI: 0.076-0.906, p = 0.034), longer duration of infertility (OR: 0.967, 95% CI: 0.942-0.993, p = 0.012), endometriosis (versus unexplained infertility; OR: 0.177, 95% CI: 0.040-0.775, p = 0.022) and endometrial thickness below 7 mm (OR: 0.114, 95% CI: 0.015-0.862, p = 0.035) were unfavorable factors to predict clinical pregnancy.Women with old age, longer duration of infertility, the presence of endometriosis or thin endometrium in the preovulatory phase may have unfavorable outcomes during the first four IUI cycles.

Objectives: To compare plasma kisspeptin, serum leptin, and serum retinol-binding protein 4 (RBP4) levels in women with and without polycystic ovary syndrome (PCOS) and to correlate these among each other and with clinical, hormonal, and metabolic parameters. Methods: Ninety women, including 54 women with PCOS and 36 without PCOS, participated in this study. For all patients, history and physical examinations were performed and blood samples were collected between days 3 and 8 of a spontaneous bleeding episode in the PCOS group and during normal menses of controls. Plasma kisspeptin, serum leptin, and serum RBP4 levels were measured using specific commercial assays. Results: Kisspeptin, leptin, and RBP4 levels were significantly higher in the PCOS group than in controls. Kisspeptin and RBP4 levels were significantly higher among obese PCOS patients than controls. Leptin levels were higher among obese PCOS patients than non-obese PCOS patients or controls. Kisspeptin and leptin levels of PCOS patients were significantly correlated with RBP4 levels. When only obese PCOS patients were analyzed, kisspeptin levels correlated with only the free androgen index. Conclusions: These findings suggest that kisspeptin, leptin, and RBP4 are associated with metabolic disturbances in women with PCOS.

Because energy production involves oxidative phosphorylation, mitochondria are major sources of reactive oxygen species in the cell. Recent findings indicate that mitochondrial DNA (mtDNA) variants may play a role in the etiology of certain autoimmune and chronic inflammatory diseases. The aim of this study was to investigate the possible association between mtDNA polymorphisms and susceptibility to endometriosis. This study included 198 patients with histologically confirmed endometriosis and 167 patients without endometriosis as controls. Common variants of mtDNA at nt10398 (A/G transition), nt13708 (G/A transition), and nt16189 (T/C transition) were detected using polymerase chain reaction. An association study was performed with a chi-square test and logistic regression analysis. The prevalence of the mtDNA nt16189 variant was higher in patients with endometriosis (46.0%, 91 of 198) than in controls (34.7%, 58 of 167) (p=0.030) with odds ratio (OR) of 1.98 (95% confidence interval [CI]: 1.04-3.78). A combination of the 10398 and 16189 variants was also associated with increased risk for endometriosis (OR=1.90, 95% CI: 1.13-3.18, p=0.015). These associations remained significant even after adjusting for age and body mass index. Our data strongly suggest that the mtDNA 16189 variants and the combination of mtDNA 16189 and 10398 variants increase susceptibility to endometriosis.

Background: Cartilage oligomeric matrix protein (COMP) is a biomarker for joint destruction and its serum levels are used for assessing therapeutic efficacy. This study aims to compare changes in serum COMP levels in postmenopausal women with osteopenia/osteoporosis receiving estrogen and alendronate. Methods: A total of 62 postmenopausal women diagnosed with osteopenia or osteoporosis were treated with either estrogen (17β-estradiol 1 mg, n = 30) or bisphosphonate (alendronate 5 mg, n = 32) for 6 months. The controls were healthy postmenopausal women (n = 30). Serum COMP and osteocalcin levels were measured at baseline and after 6 months of treatment. Results: Estrogen decreased levels of COMP at 6 months compared to baseline levels (–8.35 ± 19.38%), whereas the bisphosphonate and control groups resulted in no significant changes (–5.50 ± 18.69 and –1.49 ± 25.34%, respectively). Concentrations of osteocalcin decreased significantly in both treatment groups (estrogen –25.60 ± 24.42% and alendronate –13.76 ± 23.89%, respectively). There was a significant positive correlation between changes after 6 months in COMP and osteocalcin (R = 0.48, p = 0.002). Conclusions: Postmenopausal women treated with estrogen showed significantly decreased levels of COMP after 6 months. Estrogen might provide a further treatment modality in the prevention of joint destruction.

Beta-amyloid (Aβ) is a major pathogenic peptide for Alzheimer's disease (AD) and is generated by the processing of amyloid precursor protein (APP). The Aβ monomers aggregate into oligomeric and fibrillar forms which have been implicated as the toxic species inducing the neuronal dysfunction. Brown algae Ecklonia cava is known for its anti-oxidant and anti-inflammatory functions. Therefore, we tested the effect of E. cava extract on the production and aggregation of Aβ peptides. The butanol extract of E. cava reduced Aβ secretion from HEK293 cells expressing APP with Swedish mutation and increased soluble APPα and C-terminal fragment-α (CTFα), of which activity was similar to BACE (β-site of APP cleaving enzyme) inhibitors. Furthermore, the extract inhibited Aβ oligomerization, particularly mid-size oligomer formation, confirmed by the ultrastructural morphology. Congo red, thioflavin T assays, and electron microscopy showed that the extract inhibited Aβ fibril formation effectively. Finally, the extract protected primary cortical neurons from various Aβ-induced cell deaths, especially oligomer-induced death. Although further study is needed to test the effectiveness of the extract in vivo, our results demonstrate, for the first time, that the butanol extract of E. cava could be used as an anti-Aβ agent for AD therapeutics.

Non-steroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1) is involved in cellular processes such as inflammation, apoptosis and tumorigenesis. However, little is known about the expression and function of NAG-1 in the endometrium. This study aimed to evaluate the expression of NAG-1 in the endometrium and in the absence or presence of endometriosis and to investigate the effect of celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, on NAG-1 mRNA levels and apoptosis in human endometrial stromal cells (HESCs).Eutopic endometrial samples were obtained during surgery from 40 patients with, and 40 patients without, endometriosis. Real-time PCR was used to quantify NAG-1 mRNA levels and immunohistochemistry was used to localize NAG-1 protein in the endometrium. To investigate the effects of celecoxib, HESCs were isolated and cultured with different concentrations of celecoxib or with 100 µM celecoxib at different times. Apoptosis was assessed by flow cytometry.NAG-1 mRNA levels and immunoreactivity showed cyclical changes through the menstrual cycle, increasing during the late secretory and menstrual phases. NAG-1 mRNA and protein levels were significantly lower in patients with endometriosis, compared with the control group. Celecoxib induced NAG-1 mRNA levels and apoptosis in cultured HESCs, with the effects dependent on drug concentrations and duration of treatment. Celecoxib treatment had no effect on prostaglandin E(2) levels in the culture supernatants.NAG-1 may be important in maintaining homeostasis in the normal endometrium and alterations in NAG-1 expression may be associated with the establishment of endometriosis. NAG-1 might be a therapeutic target for endometriosis.

The levonorgestrel-releasing intrauterine system (LNG-IUS) is effective in the treatment of dysmenorrhea associated with adenomyosis. However, the mechanism of pain relief of LNG-IUS in patients with adenomyosis is unclear. We aimed to investigate the effects of LNG-IUS on the expression of nerve growth factor (NGF) and its receptors, NGFR p75 and TrkA in patients with adenomyosis. Endometrial and myometrial tissues were prepared from 17 LNG-IUS-treated patients and 15 hormonally untreated patients who had undergone hysterectomies for adenomyosis. Immunohistochemistry with antibodies against NGF, NGFR p75, and TrkA, was performed. The expression of NGF, NGFR p75, and TrkA in endometrium and myometrium of LNG-IUS-treated patients was significantly decreased compared to those of hormonally untreated patients. Our findings may indicate that the suppression of NGF and its receptors by LNG-IUS is another possible mechanism of relieving pain in patients with adenomyosis.

Although the pathophysiology of adenomyosis has not been clarified, it is thought to be related to ectopic endometrium, which depends on hormonal regulation. The levonorgestrel-releasing intrauterine system (LNG-IUS) is effective for the medical treatment of adenomyosis. However, the underlying molecular mechanisms by which LNG-IUS ameliorates adenomyosis pathology remain unclear. This study was designed to compare the expression levels of steroid receptor coregulators in human endometrium of control and participants with adenomyosis and to determine whether LNG-IUS modulated their expression. Immunohistochemistry with H-scores was performed. Steroid receptor coactivators were shown to have significantly decreased expressions at the secretory phase in the LNG-IUS group when compared to the other groups. Expression of transcriptional intermediary factor 2 was lower in the LNG-IUS group than in both the control group (P = .015) and the untreated adenomyosis group (P = .019) during the secretory phase. Amplified in breast cancer 1 expression was higher in the stromal cells of the untreated adenomyosis group than in those of the controls (P = .017) during the secretory phase; however, levels were lower in the LNG-IUS group (P = .005). Nuclear receptor corepressor expression increased during the proliferative phase and decreased during the secretory phase in untreated adenomyosis; this pattern was reversed in the control and LNG-IUS groups. Thus, an altered expression of steroid receptor coregulators may play a role in adenomyosis development and treatment.

Polycystic ovary syndrome (PCOS) is associated with multiple risk factors for cardiovascular disease (CVD), including insulin resistance, type 2 diabetes mellitus, obesity, hypertension, and dyslipidemia. In addition, hyperandrogenism may contribute to the pathogenesis of CVD, independent of obesity and insulin resistance. We investigated serum levels of asymmetric dimethylarginine (ADMA), apelin, and tumor necrosis factor (TNF)-α as CVD risk markers and their relationship with hyperandrogenism in non-obese women with PCOS. In this study were included 82 non-obese women with PCOS and 33 controls. Women with PCOS were further divided into two groups: women with hyperandrogenism (HA-PCOS, n=37) and those without hyperandrogenism (NA-PCOS, n=45). Serum ADMA, apelin, and TNF-α levels were compared among the three groups and their relationship with hyperandrogenism was evaluated. Serum ADMA levels were significantly higher in the HA-PCOS group than in the NA-PCOS and control groups (0.45 ± 0.09 vs. 0.38 ± 0.08 vs. 0.40 ± 0.07; P

background: Recently, proteomic technologies have demonstrated that several proteins are differently expressed in various body fluids of patients with endometriosis compared with those without this condition. The aim of this study was to investigate proteins secreted in urine of patients with endometriosis using proteomic techniques in order to identify potential markers for the clinical diagnosis of endometriosis. methods: Urine samples were collected from women undergoing laparoscopy for different indications including pelvic masses, pelvic pain, suspicious endometriosis, infertility and diagnostic evaluation. Proteomic techniques and mass spectrometry were used to identify proteins secreted in the urine of the patients with and without endometriosis and quantification of identified protein was performed using western blot and specific commercial sandwich enzyme-linked immunosorbent assays (ELISA). results: Twenty-two protein spots were differentially expressed in the urine of patients with and without endometriosis, one of which was identified as urinary vitamin D-binding protein (VDBP). ELISA quantification of urinary VDBP corrected for creatinine expression (VDBPCr) revealed that urinary VDBP-Cr was significantly greater in patients with endometriosis than in those without (111.96+ 74.59 versus 69.90+ 43.76 ng/mg Cr, P ¼ 0.001). VDBP-Cr had limited value as a diagnostic marker for endometrioisis (Sensitivity 58%, Specificity 76%). When combined with serum CA-125 levels (the product of serum CA-125 and urinary VDBP-Cr), it did not significantly increase the diagnostic power of serum CA-125 alone. conclusions: Urinary VDBP levels are elevated in patients with endometriosis. They have limited value as a potential diagnostic biomarker for endometriosis but suggest it would be worthwhile to investigate other urinary proteins for this purpose.

This study aimed to investigate the clinical value of pre-treatment leukocyte differential counts and the prediction of endometrial cancer using leukocyte markers.Medical records of 238 women with pathologically confirmed endometrial cancer between March 2000 and June 2009 at two Korean hospitals were reviewed and compared to 596 healthy people visiting the Health Promotion Center in Gangnam Severance Hospital. For all study subjects, leukocyte differential counts and CA125 levels in serum obtained prior to operation were recorded. Multiplication of neutrophil and monocyte (MNM) was determined by multiplying neutrophil and monocyte counts then dividing by 10000. Differences between endometrial cancer patients and healthy controls were compared. The sensitivity and specificity for each marker as well as the combined use of CA125 and other leukocyte markers were assessed using receiver operating characteristic curves.Mean white blood cell (WBC) counts were 6676 (6440-6913) cells/µL in endometrial cancer patients compared to 5663 (5542-5784) cells/µL in healthy controls (P0.001). The area under curve (AUC) for CA125 was 0.689 with a sensitivity of 49.13% and specificity of 83.1% using an optimal cut-off value of 18.7U/mL. The AUC for MNM was 0.696 with a sensitivity of 62.9% and specificity of 69.1%. The combination of CA125 and MNM showed a higher AUC of 0.760 than use of CA125 or MNM alone.The combination of MNM and CA125 is a simple and cost-effective method for predicting endometrial cancer.

The aim of this study was to evaluate the effects of red ginseng (RG) on menopausal symptoms and cardiovascular risk factors in postmenopausal women.A randomized, placebo-controlled, double-blind clinical trial was conducted with postmenopausal women between the ages of 45 and 60 years. A total of 72 women were randomly assigned to either an RG group (supplemented with 3 g of RG, including 60 mg of ginsenosides, per day) or a placebo group for 12 weeks. We analyzed changes in menopausal symptoms (the Kupperman index and the menopause rating scale), cardiovascular risk factors (lipid profiles, high-sensitivity C-reactive protein, and carotid intima-media thickness), and serum estradiol levels from baseline to 12 weeks.Significant improvements in the Kupperman index (P = 0.032) and in the menopause rating scale (P = 0.035) scores were observed in the RG group compared with the placebo group. Total cholesterol (P = 0.009) and low-density lipoprotein cholesterol (P = 0.015) significantly decreased in the group receiving RG. The RG group also showed a significant decrease in carotid intima-media thickness (P = 0.049). Serum estradiol levels were not influenced by RG supplementation.RG could be an attractive herbal dietary supplement for relieving menopausal symptoms and conferring favorable effects on markers of cardiovascular disease in postmenopausal women.

To date, protein profiles for hepatocellular carcinomas and cholangiocarcinomas have not been systematically evaluated and compared with each other in an unbiased way. Thirty-six hepatocellular carcinomas and adjacent normal tissue samples were analyzed using histology-directed, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). Four cholangiocarcinomas and adjacent normal tissue samples were also evaluated. Tissue samples were sectioned at 10 µm, with 1-3 sections thaw-mounted on a conductive indium tin oxide-coated glass slide. Sinapinic acid was manually deposited on areas of each tissue section enriched by epithelial cells, either tumor or normal, and mass spectra were acquired using a MALDI-time of flight instrument. According to class prediction analysis, average prediction accuracy in test sets (composed of 18 hepatocellular carcinoma-normal pairs) ranged from 93.0 to 95.8%. Cholangiocarcinomas and hepatocellular carcinomas had different protein profiles, as evidenced by average prediction accuracy of95% in the test set for all classifiers. Permutation P-values for 0.632 + bootstrap cross validated misclassification rates (at feature selection P0.001) were less than 0.05 for predicting p53 immunostaining status. We conclude that MALDI MS profiles may be useful in assisting with the diagnosis and the differential diagnosis of primary liver cancers.

The aim of this study is to evaluate the expression of vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1) in peritoneal fluid (PF), peritoneal endometriotic lesions and eutopic endometrial tissues of patients with endometriosis. Peritoneal fluid, peritoneal endometriotic lesions and eutopic endometrial samples from patients with endometriosis, and peritoneal fluid, peritoneal tissue and endometrial samples from patients without endometriosis were obtained during an operative laparoscopy. The mean PF concentrations of VEGF and sFlt-1 were significantly higher in patients with endometriosis than in the controls. In the peritoneal tissue, the expressions of VEGF and sFlt-1 were significantly higher, where the expression of sFlt-1 in endometrium was significantly lower in patients with endometriosis. These findings indicate that not only abnormal expressions of angiogenic factors, but also aberrant expressions of antiangiogenic factors in the peritoneal and endometrial environment seem to be involved in the pathogenesis of endometriosis.

Background Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) has been demonstrated to be useful for molecular profiling of common solid tumors. Using recently developed MALDI matrices for lipid profiling, we evaluated whether direct tissue MALDI MS analysis on proteins and lipids may classify human breast cancer samples according to the intrinsic subtype. Methods Thirty-four pairs of frozen, resected breast cancer and adjacent normal tissue samples were analyzed using histology-directed, MALDI MS analysis. Sinapinic acid and 2,5-dihydroxybenzoic acid/α-cyano-4-hydroxycinnamic acid were manually deposited on areas of each tissue section enriched in epithelial cells to identify lipid profiles, and mass spectra were acquired using a MALDI-time of flight instrument. Results Protein and lipid profiles distinguish cancer from adjacent normal tissue samples with the median prediction accuracy of 94.1%. Luminal, HER2+, and triple-negative tumors demonstrated different protein and lipid profiles, as evidenced by permutation P values less than 0.01 for 0.632+ bootstrap cross-validated misclassification rates with all classifiers tested. Discriminatory proteins and lipids were useful for classifying tumors according to the intrinsic subtype with median prediction accuracies of 80.0-81.3% in random test sets. Conclusions Protein and lipid profiles accurately distinguish tumor from adjacent normal tissue and classify breast cancers according to the intrinsic subtype.

Oxidized low-density lipoprotein (oxLDL) is a key autoantigen in atherosclerosis. The genetic structures and pathogenic roles of autoantibodies against this protein remain to be established. In this study, we cloned several monoclonal IgG autoantibody Fab fragments specific for oxLDL from peripheral blood lymphocytes of atherosclerosis patients, using phage display technology. The sequences of their variable regions were determined at the cDNA level. The closest germline counterparts for the heavy chains belonged to the VH3 or VH1 family. The sequences and lengths of complementarity-determining regions (CDR)3-VH were diverse, and frequent mutations of positively charged amino acids (particularly arginine) over entire VH and VL sequences were observed. It is proposed that anti-oxLDL autoantibody formation is driven by antigens. Among the Fabs, P2-8 and P3-175 bound to both MDA-LDL and Cu-oxLDL, and inhibited the uptake of oxLDL by macrophages, suggesting the epitope(s) recognized by the Fabs is a part of ligands on oxLDL that is involved in uptake by macrophage scavenger receptor. These human autoantibody Fabs require detailed investigation to ascertain their potential as agents for clinical applications.