Metabolic Syndrome as a Risk Factor of Endometrial Cancer: A Nationwide Population-Based Cohort Study of 2.8 Million Women in South Korea.

Background: A positive relationship was reported between metabolic syndrome and the risk of endometrial cancer. Studies on the relationship between metabolic syndrome and endometrial cancer have been mainly conducted in post-menopausal women. We aimed to investigate the risk of endometrial cancer according to metabolic syndrome and menopausal status using the Korean nationwide population-based cohort. Methods: We enrolled 2,824,107 adults (endometrial cancer group; N = 5,604 and control group; N= 2,818,503) from the Korean National Health Insurance Service checkup database from January 1 to December 31, 2009. The median follow-up duration was 8.37 years. Metabolic syndrome was diagnosed as having at least three of the following five components: abdominal obesity, hypertriglyceridemia, low levels of high-density lipoprotein cholesterol, raised blood pressure, and hyperglycemia. Multivariate Cox proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) to estimate endometrial cancer risk. Results: The endometrial cancer risk was higher in the metabolic syndrome group than that in the non-metabolic syndrome group (HR, 1.362; 95% CI, 1.281-1.449). The association between metabolic syndrome and endometrial cancer risk was significant in the premenopausal subgroup (HR, 1.543; 95% CI, 1.39-1.713) and postmenopausal subgroup (HR, 1.306; 95% CI, 1.213-1.407). The incidence of endometrial cancer was more closely related to metabolic syndrome components in the pre-menopausal subgroup than those in the post-menopausal subgroup (for waist circumference, blood pressure, triglycerides and high-density lipoprotein cholesterol, all p for interaction <0.0001 respectively, and for fasting blood glucose, p for interaction 0.0188). The incidence of endometrial cancer positively correlated with the number of metabolic syndrome components (log-rank p <0.0001). Conclusion: Our large population-based cohort study in Korean women suggests that metabolic syndrome and its accumulated components may be risk factors for endometrial cancer, particularly in the pre-menopausal women.

Risk of female-specific cancers according to obesity and menopausal status in 2•7 million Korean women: Similar trends between Korean and Western women.

BACKGROUND: Studies examining the relationship between obesity and female-specific cancers have been mainly conducted in Western populations. We aimed to investigate the risk of female-specific cancers according to obesity and menopausal status using a nationwide cohort in Korea. METHODS: We identified 2,708,938 women from the National Health Insurance Service cohort, and obtained baseline body mass index (BMI), waist circumference (WC), and other healthcare data, measured and collected during a health examinations and cancer-screening survey. By setting a normal weight/WC group (BMI, 18•5-22•9 kg/m2 or WC, 80•0-84•9 cm) as the reference, we conducted multivariate analyses using the Cox proportional hazard model to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) for each cancer. FINDINGS: The total follow-up duration was 22389854•63 person-years. In post-menopausal women, the risk of breast, endometrial, and ovarian cancers significantly increased as the BMI classification level increased from normal to class II obesity (aHRs [95% CIs], 1•49 [1•38-1.61], 2•11 [1•81-2•46], and 1•38 [1•20-1•58], respectively). The risk of breast and endometrial cancers also increased as the WC classification increased from < 75•0 to ≥ 95•0 cm. With a WC of 80•0-84•9 cm as the reference, the lowest risk of breast and endometrial cancers was observed in WC < 75•0 cm (aHRs [95% CIs], 0•85 [0•81-0•89] and 0•75 [0•67-0•84], respectively) while the highest risk was observed in WC ≥ 95•0 cm (aHRs [95% CIs], 1•19 [1•10-1•29] and 1•56 [1•33-1•82], respectively). In pre-menopausal women, the risk of breast cancer significantly decreased in those with class I and II obesity compared to those with normal BMI (aHRs [95% CIs], 0•96 [0•92-0•999] and 0•89 [0•81-0•97], respectively), whereas the trends of endometrial and ovarian cancer incidence in pre-menopausal women were similar to those observed in post-menopausal women. For cervical cancer, only class II obesity was significantly associated with increased risks in both post-menopausal and pre-menopausal women (aHRs [95% CIs], 1•18 [1•01-1•39] and 1•27 [1•02-1•57], respectively). INTERPRETATION: In this large population-based cohort study in Korean women, we observed that the impact of obesity on the development of female-specific cancers differs according to the malignancy type and menopausal status. Similar trends were observed between Korean and Western women. FUNDING: The Korea Health Industry Development Institute (no. HI16C2037).

Enhanced Susceptibility to Breast Cancer in Korean Women With Elevated Serum Gamma-Glutamyltransferase Levels: A Nationwide Population-Based Cohort Study.

BACKGROUND: The incidence of breast cancer has been gradually increasing in Korea. Recently, the elevated level of serum gamma-glutamyltransferase (GGT) has emerged to be associated with the development and progression of some malignancies. This study aimed to determine the effect of serum GGT levels on the risk of developing breast cancer in Korean women. METHODS: We used National Health Insurance Service Health Checkup data to examine the association between serum GGT levels and breast cancer development in Korean women. Women aged 40 years or older who participated in the Korean National Health Screening Examination between January 2009 and December 2009 and who did not develop any cancer within 1-year post examination were included in this analysis (n = 3,109,506). Cox proportional hazard regression analysis was conducted to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Overall, an elevated serum GGT level was associated with the increased risk of developing breast cancer; compared to the Q1 group, the Q4 group showed a significantly increased breast cancer risk (HR: 1.120,95% CI: 1.08-1.162). Such a relationship was stronger in post-menopausal women than pre-menopausal women (HR: 1.173, 95% CI: 1.107-1.243; HR: 1.070, 95% CI:1.019-1.124). Women with a high GGT level (Q4) were also at an increased risk of developing carcinoma in situ (CIS) (HR: 1.114, 95% CI: 1.04-1.192). In post-menopausal women, the Q4 group also exhibited higher CIS risk (HR: 1.266, 95% CI: 1.132-1.416). However, no significant difference in the risk of developing CIS was observed between the Q1 and Q4 groups in pre-menopausal women. Further analysis revealed that obese, post-menopausal women with a high GGT level (Q4) were associated with an increased risk of developing breast cancer (HR: 1.214, 95% CI: 1.125-1.31) and CIS (HR: 1.348, 95% CI: 1.159-1.569). CONCLUSIONS: Our study results demonstrate that increased serum GGT level is a risk factor for developing breast cancer. The post-menopausal women group with obesity and elevated serum GGT level showed the highest incidence of breast cancer. Thus, serum GGT concentration could be a novel and potential risk factor for breast cancer. Further validation in different ethnic groups would be warranted.

Increasing serum gamma-glutamyltransferase level accompanies a rapid increase in the incidence of endometrial cancer in Korea: A nationwide cohort study.

OBJECTIVE: This study aimed to determine the association of serum GGT levels with the risk of developing endometrial cancer. Women's obesity and menopausal status were also taken into account in our analysis. METHODS: We used a nationwide cohort to examine the association between serum GGT levels and endometrial cancer development in Korean women. Data were retrieved from the Korean National Health Insurance Service (NHIS) healthcare system. Women aged over 19 years who participated in the Korea National Health Screening Examination in 2009 and were not diagnosed with endometrial cancer 1-year post-examination were included in our study (n = 2,736,588). RESULTS: Obese (BMI, ≥25 kg/m2) women with increased GGT levels were at high risk of endometrial cancer (HR = 1.415, 95% CI: 1.236-1.621). Interestingly, in pre-menopausal women, high GGT level (Q4) was associated with the increased endometrial cancer risk only for obese women (HR = 1.482, 95% CI: 1.205-1.821). In post-menopausal women, only a high GGT level (Q4) was also associated with the increased cancer risk for obese women (HR = 1.313, 95% CI: 1.096-1.573). We observed a significant association between high GGT levels and increased risk of endometrial cancer in pre-menopausal women with abdominal obesity (WC, ≥85 cm) (HR = 1.647, 95% CI: 1.218-2.227). CONCLUSIONS: Increased GGT level is an independent risk factor of endometrial cancer, especially for post-menopausal women and obese pre-menopausal women. These results may suggest that serum GGT levels might be useful in the risk stratification of endometrial cancer. Adopting a healthy lifestyle for lowering serum GGT level is warranted, especially for women with a higher risk of developing endometrial cancer.

Piceatannol Is Superior to Resveratrol at Suppressing Adipogenesis in Human Visceral Adipose-Derived Stem Cells.

Resveratrol (3,4',5-trans-trihydroxystilbene) and piceatannol (3,3',4',5-trans-tetraphydroxystilbene) are major stilbene compounds that are predominantly present in various natural foods, such as berries and fruits. Both phytochemical compounds are consumed as dietary supplements to prevent various metabolic diseases and for their anti-aging properties. Adipose-derived stem cells from human visceral adipose tissue (vASCs) are a useful in vitro model for evaluating their adipogenic effect. Treatment with resveratrol and piceatannol significantly inhibited lipid accumulation in vASCs. Their effective concentrations were 5, 10, and 20 µM for inhibiting adipogenesis of vASCs. Interestingly, despite the similar chemical structures of the two compounds, piceatannol showed a higher anti-adipogenic effect at 20 µM than resveratrol in vASCs. Moreover, the inhibitory capacity of lipid droplet generation was higher for piceatannol at 20 µM than that of resveratrol. Piceatannol significantly attenuated the expression level of adipogenic markers (e.g., CCAAT/enhanced binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ (PPARγ), and adipocyte fatty acid binding protein (aP2)) compared to resveratrol at the mRNA and protein levels. These results suggest that piceatannol is a superior anti-adipogenic compound compared to resveratrol in the vASC model of visceral obesity.

Sulforaphene Suppresses Adipocyte Differentiation via Induction of Post-Translational Degradation of CCAAT/Enhancer Binding Protein Beta (C/EBPß).

Adipocyte differentiation (adipogenesis) is a crucial process that determines the total number and size of mature adipocytes that will develop. In this study, the anti-adipogenic effect of sulforaphene (SFEN), a dietary isothiocyanate (ITC) derived from radish, is investigated both in 3T3-L1 pre-adipocytes and in human adipose tissue-derived stem cells. The results revealed that SFEN significantly inhibit adipogenic cocktail-induced adipocyte differentiation and lipid accumulation at the early stage of adipogenesis. Additionally, the effects are more potent compared to those of other ITCs derived from various cruciferous vegetables. As a related molecular mechanism of action, SFEN promotes the post-translational degradation of CCAAT/enhancer-binding protein (C/EBP) ß by decreasing the stability of C/EBPß, which is responsible for decreasing the expression of master regulatory proteins such as peroxisome proliferator-activated receptor γ and C/EBPα. Collectively, these results suggest that the intake of SFEN-enriched natural materials could be helpful as a strategy for preventing obesity.

Decursin and Decursinol Angelate Suppress Adipogenesis through Activation of ß-catenin Signaling Pathway in Human Visceral Adipose-Derived Stem Cells.

Visceral adiposity is closely associated with metabolic disorders and cardiovascular diseases. Angelica gigas Nakai (AGN) has been reported to possess anti-obesity effects and higher amounts of coumarin compounds are present in AGN. However, the active compounds suppressing adipogenesis in AGN and mechanisms of action have not been investigated in adipose-derived stem cells (ASCs) isolated from visceral adipose tissue (VAT). Among four coumarin compounds of AGN, decursin (D) and decursinol angelate (DA) significantly inhibited adipocyte differentiation from ASCs. D and DA downregulated CCAAT/enhancer binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ (PPARγ), adipocyte fatty acid binding protein (aP2), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) at both mRNA and protein levels. Next, treatment with adipogenic differentiation medium (ADM) on ASCs downregulated ß-catenin expression at protein level, while addition of D and DA could restore protein expression and nuclear translocation of ß-catenin suppressed by ADM. D and DA treatment on ADM treated ASCs increased inhibitory phosphorylation of Glycogen synthase kinase (GSK)-3ß, thereby preventing ß-catenin from degradation. Additionally, si-ß-catenin transfection significantly upregulated protein expression of C/EBPα and PPARγ, alleviating the anti-adipogenic effect of D and DA on ADM treated ASCs. Overall, D and DA, active compounds from AGN, suppressed adipogenesis through activation of ß-catenin signaling pathway in ASCs derived from human VAT, possibly using as natural anti-visceral adiposity agents.

Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells.

Mitochondria undergo fission and fusion continually for survival through the course of cellular adaption processes in response to changes in the surrounding environment. Dysregulated mitochondrial dynamics has been reported in various diseases including cancer. Under hypoxic conditions (<1% O2), the relationship between mitochondrial dynamics and sensitivity to cisplatin (CDDP) was examined in ovarian cancer cells. We found that hypoxia promoted mitochondrial fission and CDDP resistance in ovarian cancer cells. Hypoxia-induced reactive oxygen species (ROS) caused an increase in mitochondrial fission, a response abolished by free radical scavenging with N-acetylcysteine (NAC) and Trolox. Also, treatment of hydrogen peroxide (H2O2) decreased inhibitory p-Drp1 (Ser637) content and increased mitochondrial fission. Suppression of mitochondrial fission enhanced the CDDP sensitivity of hypoxic ovarian cancer cells. Lastly, in tumor spheroids from malignant ascites or tissues of patients with advanced-stage ovarian cancer, pretreatment with Mdivi-1 increased the CDDP sensitivity. Taken together, our results implicate that hypoxia-induced ROS trigger mitochondrial fission and CDDP resistance through downregulation of p-Drp1 (Ser637) and Mfn1 in ovarian cancer cells. Inhibition of Drp1 by Mdivi-1 treatment or si-Drp1 transfection increased CDDP sensitivity of ovarian cancer cells under hypoxia. Therefore, mitochondrial dynamics of cancer cells adapting to the hypoxic tumor microenvironment could be a potential target for anticancer therapy.

Tumour microenvironment on mitochondrial dynamics and chemoresistance in cancer.

Mitochondria, evolutionally acquired symbionts of eukaryotic cells, are essential cytoplasmic organelles. They are structurally dynamic organelles that continually go through fission and fusion processes in response to various stimuli. Tumour tissue is composed of not just cancer cells but also various cell types like fibroblasts, mesenchymal stem and immune cells. Mitochondrial dynamics of cancer cells has been shown to be significantly affected by features of tumour microenvironment such as hypoxia, inflammation and energy deprivation. The interactions of cancer cells with tumour microenvironment like hypoxia give rise to the inter- and intratumoural heterogeneity, causing chemoresistance. In this review, we will focus on the chemoresistance by tumoural heterogeneity in relation to mitochondrial dynamics of cancer cells. Recent findings in molecular mechanisms involved in the control of mitochondrial dynamics as well as the impact of mitochondrial dynamics on drug sensitivity in cancer are highlighted in the current review.

Differential abilities of Korean soybean varieties to biosynthesize glyceollins by biotic and abiotic elicitors.

Glyceollins synthesized in soybeans that are exposed to biotic or abiotic stress have been reported to have health benefits. Considering that glyceollins are de novo synthesized from daidzein via several enzymatic steps and that isoflavone concentration widely varies among soybean varieties, the abilities of 60 soybean cultivars to synthesize glyceollins were compared under different elicitation conditions. Soybeans accumulated glyceollins differentially depending upon the cultivar when elicited with Aspergillus sojae. Contrary to our hypothesis that high isoflavone varieties may accumulate glyceollins more efficiently upon elicitation, glyceollin accumulation in response to fungal elicitation was not related with the concentration of either total isoflavones or daidzein in soybeans. Rather the glyceollin levels were significantly affected by soybean cultivar and most effectively increased by fungal infection. The data suggest that the selection of a strong fungal elicitor and a soybean cultivar with genotype that highly expresses the genes involved in glyceollin biosynthesis is essential for efficient glyceollin production.

Corrigendum to "Effects of an Aqueous Extract of Dangguijagyagsan on Serum Lipid Levels and Blood Flow Improvement in Ovariectomized Rats".

[This corrects the article DOI: 10.1155/2014/497836.].

Sagunja-Tang Improves Lipid Related Disease in a Postmenopausal Rat Model and HepG2 Cells.

The present study was conducted to investigate the effect of Sagunja-tang on the lipid related disease in a rat model of menopausal hyperlipidemia and lipid accumulation in methyl-ß-cyclodextrin-induced HepG2 cells. In in vivo study using menopausal hyperlipidemia rats, Sagunja-tang reduced retroperitoneal and perirenal fat, serum lipids, atherogenic index, cardiac risk factor, media thickness, and nonalcoholic steatohepatitis score, when compared to menopausal hyperlipidemia control rats. In HepG2 cells, Sagunja-tang significantly decreased the lipid accumulation, total cholesterol levels, and low-density/very-low-density lipoprotein levels. Moreover, Sagunja-tang reversed the methyl-ß-cyclodextrin-induced decrease in the protein levels of critical molecule involved in cholesterol synthesis, sterol regulatory element binding protein-2, and low-density lipoprotein receptor and inhibited protein levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase as well as activity. Phosphorylation level of AMP-activated protein kinase was stimulated by Sagunja-tang. These results suggest that Sagunja-tang has effect on inhibiting hepatic lipid accumulation through regulation of cholesterol synthesis and AMPK activity in vitro. These observations support the idea that Sagunja-tang is bioavailable both in vivo and in vitro and could be developed as a preventive and therapeutic agent of hyperlipidemia in postmenopausal females.

Effects of an aqueous extract of dangguijagyagsan on serum lipid levels and blood flow improvement in ovariectomized rats.

Dangguijagyagsan (DJS), a traditional herbal prescription, has long been used to treat menopause-related symptoms. We identified the cardioprotective effects of an aqueous extract of DJS using an ovariectomized (OVX) and ferric chloride- (FeCl-) induced carotid thrombosis rat model. Female Sprague-Dawley (SD) rats were ovariectomized or Sham-operated (Sham-control). The ovariectomized rats were divided into three groups: OVX with saline (OVX-control), aspirin 30 mg/kg/day (OVX-ASA), and DJS 100 mg/kg/day (OVX-DJS). The treatments were administered for 5 weeks. Then, blood samples were collected to analyze the serum lipid levels and platelet aggregation. The topical application of 40% FeCl3 induced intravascular thrombosis, which was used to test thrombotic occlusion and for histological examination. Body weight and the levels of total cholesterol (TC), triglyceride (TG), and LDL-cholesterol (LDL-C) increased in the OVX rats. These effects were reduced by ASA and DJS treatment. In addition, ASA and DJS treatment significantly inhibited platelet aggregation. These treatments also increased time to occlusion and decreased both thrombus size and the presence of collagen fibers in surrounding vessel walls compared with the Sham-control and OVX-control groups. These results suggest that DJS has beneficial effects in terms of preventing cardiovascular disease in menopausal woman because it can reduce the serum lipid levels and improve blood flow by inhibiting platelet aggregation and thrombus formation.

Dehydroglyasperin C, a component of liquorice, attenuates proliferation and migration induced by platelet-derived growth factor in human arterial smooth muscle cells.

Liquorice is one of the botanicals used frequently as a traditional medicine in the West and in the East. Platelet-derived growth factor (PDGF)-BB is involved in the development of CVD by inducing abnormal proliferation and migration of vascular smooth muscle cells. In our preliminary study, dehydroglyasperin C (DGC), an active compound of liquorice, showed strong antioxidant activity. Since phytochemicals with antioxidant activities showed beneficial effects on chronic inflammatory diseases, the present study aimed to investigate the effects of DGC on PDGF-induced proliferation and migration of human aortic smooth muscle cells (HASMC). Treatment of HASMC with DGC for 24 h significantly decreased PDGF-induced cell number and DNA synthesis in a dose-dependent manner without any cytotoxicity, as demonstrated by the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide test and thymidine incorporation. Upon cell cycle analysis, DGC blocked the PDGF-induced progression through the G0/G1 to S phase of the cell cycle, and down-regulated the expression of cyclin-dependent kinase (CDK); 2, cyclin E, CDK4 and cyclin D1. Furthermore, DGC significantly attenuated PDGF-stimulated phosphorylation of PDGF receptor-b, phospholipase C-g1, AKT and extracellular-regulated kinase 1/2, and DGC inhibited cell migration and the dissociation of actin filaments by PDGF. In a rat vascular balloon injury model, DGC suppressed an excessive reduction in luminal diameters and neointimal formation compared with the control group. These results demonstrate the mechanistic basis for the prevention of CVD and the potential therapeutic properties of DGC.

Neuroprotective effects of dehydroglyasperin C through activation of heme oxygenase-1 in mouse hippocampal cells.

Licorice, the root of the Glycyrrhiza species ( Glycyrrhiza uralensis Fisher), is known to have antioxidant, anti-inflammatory, antiviral, and antitumor properties. The objective of this study is to explore the neuroprotective effect of dehydroglyasperin C (DGC) against glutamate-induced oxidative stress in mouse hippocampal HT22 cells. DGC significantly reduced cytotoxicity and reactive oxygen species (ROS) generation induced by glutamate in HT22 cells, whereas DGC did not restore glutathione depletion caused by glutamate. In addition, it was further investigated whether DGC affected the expression of heme oxygenase (HO)-1, one of the major cellular antioxidant defense systems, and it was found that DGC dose-dependently increased HO-1 expression. DGC-mediated cytoprotection of HT22 neuronal cells from glutamate insult was abrogated by either HO-1 inhibitor (Tin protoporphyrin, SnPP) or AKT inhibitor (LY294002). In conclusion, the present results demonstrate for the first time that DGC protects neuronal cells against glutamate-induced oxidative injury through the induction of HO-1 expression, which is, in turn, activated maybe through Nrf2-Keap1 and PI3K/AKT signaling pathways.