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Open access

Qi Che, Xirong Xiao, Jun Xu, Miao Liu, Yongning Lu, Suying Liu and Xi Dong

Accumulating evidence revealed that the leading risk factor of endometrial cancer is exposure to endogenous and exogenous estrogens, while the exact mechanism underlying estrogen contribution to endometrial cancer progression has not been elucidated clearly. Interleukin (IL)-6 has been verified to be critical for tumor progression in several human cancers. In this study, we provided evidence that 17β-estradiol (E2) could significantly promote endometrial cancer cells viability, migration and invasion through activation of IL-6 pathway, which involved in its downstream pathway and target genes (p-Stat3, Bcl-2, Mcl-1, cyclin D1 and MMP2). Meanwhile, utilization of IL-6-neutralizing antibody could partially attenuate the increased cancer growth and invasion abilities in Ishikawa and RL95-2 endometrial cancer cell lines and an orthotopic endometrial cancer model. We established a causative link between estrogen and IL-6 signaling activation in the development of endometrial cancer. The molecular mechanism defined in this study provided the evidence that E2 promotes endometrial carcinoma progression via activating the IL-6 pathway, indicating that interruption of IL-6 might be an essential therapeutic strategy in estrogen-dependent endometrial cancer.

Open access

Tatiana V Novoselova, Peter J King, Leonardo Guasti, Louise A Metherell, Adrian J L Clark and Li F Chan

The melanocortin-2-receptor (MC2R), also known as the ACTH receptor, is a critical component of the hypothalamic–pituitary–adrenal axis. The importance of MC2R in adrenal physiology is exemplified by the condition familial glucocorticoid deficiency (FGD), a potentially fatal disease characterised by isolated cortisol deficiency. MC2R mutations cause ~25% of cases. The discovery of a MC2R accessory protein MRAP, mutations of which account for ~20% of FGD, has provided insight into MC2R trafficking and signalling. MRAP is a single transmembrane domain accessory protein highly expressed in the adrenal gland and essential for MC2R expression and function. Mouse models helped elucidate the action of ACTH. The Mc2r-knockout (Mc2r / ) mice was the first mouse model developed to have adrenal insufficiency with deficiencies in glucocorticoid, mineralocorticoid and catecholamines. We recently reported the generation of the Mrap / mice which better mimics the human FGD phenotype with isolated glucocorticoid deficiency alone. The adrenal glands of adult Mrap / mice were grossly dysmorphic with a thickened capsule, deranged zonation and deranged WNT4/beta-catenin and sonic hedgehog (SHH) pathway signalling. Collectively, these mouse models of FGD highlight the importance of ACTH and MRAP in adrenal progenitor cell regulation, cortex maintenance and zonation.

Open access

Masafumi Tetsuka and Misato Tanakadate

The bovine cumulus-oocyte complex (COC) is capable of converting cortisone, an inert glucocorticoid to active cortisol. This mechanism is mediated by 11β-hydroxysteroid oxidoreductase type 1 (HSD11B1), whose expression dramatically increases in the mature COC. In this study, we investigate the time course expression of HSD11B1 and the enzyme activity in the bovine COC undergoing maturation and fertilization in relation to key events taking place in the COC. Bovine COCs were subjected to in vitro maturation (IVM) and fertilization (IVF). The activities of HSD11B1 and HSD11B2, which mediates the opposite reaction, were measured using a radiometric conversion assay. In parallel studies, cumulus expansion, P4 production and the expression of genes associated with ovulation were measured. The reductive activity of HSD11B1 increased in the latter half of IVM and remained high during IVF, whereas the oxidative activity of HSD11B2 remained unchanged over both periods. Consequently, the net glucocorticoid metabolism in the bovine COC shifted from inactivation to activation around the time of ovulation and fertilization. The increase in HSD11B1 expression lagged behind that of P4 increase and cumulus expansion but ahead of the expressions of genes responsible for PGE2 synthesis. The reductive activity of HSD11B1 was well correlated with the cumulus expansion rate. This outcome indicates that the ability of the cumulus to activate glucocorticoids is related to its ability to synthesize hyaluronan. These results also indicate that the activation of HSD11B1 is an integral part of the sequential events taking place at the ovulation and fertilization in the bovine COC.

Open access

Mengxue Yang, Bowen Sun, Jianhui Li, Bo Yang, Jie Xu, Xue Zhou, Jie Yu, Xuan Zhang, Qun Zhang, Shan Zhou and Xiaohua Sun

Objectives

The pathogenesis of Graves’ disease (GD) remains unclear. In terms of environmental factors, GD development may be associated with chronic inflammation caused by alteration of the intestinal flora. This study explored the association of intestinal flora alteration with the development of GD among the Han population in southwest China.

Design and methods

Fifteen GD patients at the Affiliated Hospital of Zunyi Medical College between March 2016 and March 2017 were randomly enrolled. Additionally, 15 sex- and age-matched healthy volunteers were selected as the control group during the same period. Fresh stool samples were collected, and bacterial 16S RNA was extracted and amplified for gene sequencing with the Illumina MiSeq platform. The sequencing results were subjected to operational taxonomic unit-based classification, classification verification, alpha diversity analysis, taxonomic composition analysis and partial least squares-discriminant analysis (PLS-DA).

Results

The diversity indices for the GD group were lower than those for the control group. The GD group showed significantly higher abundances of Firmicutes, Proteobacteria and Actinobacillus and a higher Firmicutes/Bacteroidetes ratio than the control group. PLS-DA suggested the satisfactory classification of the flora between the GD group and the control group. The abundances of the genera Oribacterium, Mogibacterium, Lactobacillus, Aggregatibacter and Mogibacterium were significantly higher in the GD group than in the control group (P < 0.05).

Conclusions

The intestinal flora of GD patients was significantly different from that of the healthy population. Thus, alteration of intestinal flora may be associated with the development of GD.

Open access

Roberto Cosimo Melcangi, Livio Casarini, Marco Marino, Daniele Santi, Samantha Sperduti, Silvia Giatti, Silvia Diviccaro, Maria Grimoldi, Donatella Caruso, Guido Cavaletti and Manuela Simoni

Context. Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspension of the finasteride treatment, leading to a large variety of persistent side effects. Despite the severity of the clinical picture, the mechanism underlying the PFS symptoms onset and persistence is still unclear.

Objective. To study whether epigenetic modifications occur in PFS patients.

Methods. Retrospective analysis of a multicentric, prospective, longitudinal, case-control clinical trial, enrolling 16 PFS patients, compared to 20 age-matched healthy men. Main outcomes were methylation pattern of SRD5A1 and SRD5A2 promoters and concentration of eleven neuroactive steroids, measured by liquid chromatography-tandem mass spectrometry, in blood and cerebrospinal fluid (CSF) samples.

Results. SRD5A1 and SRD5A2 methylation analysis was performed in all blood samples (n=16 PFS patients and n=20 controls), in 16 CSF samples from PFS patients and in 13 CSF samples from controls. The SRD5A2 promoter was more frequently methylated in CSF of PFS patients compared to controls (56.3 versus 7.7%). No promoter methylation was detected in blood samples in both groups. No methylation occurred in the SRD5A1 promoter of both groups. Unmethylated controls compared to unmethylated SRD5A2 patients showed higher pregnenolone, dihydrotestosterone and dihydroprogesterone, together with lower testosterone CSF levels. Andrological and neurological assessments did not differ between methylated and unmethylated subjects.

Conclusions. For the first time, we demonstrate a tissue-specific methylation pattern of SRD5A2 promoter in PFS patients. Although we cannot conclude whether this pattern is prenatally established or induced by finasteride treatment, it could represent an important mechanism of neuroactive steroid levels and behavioural disturbances previously described in PFS.

Open access

Tingting Xia, Hongru Sun, Hao Huang, Haoran Bi, Rui Pu, Lei Zhang, Yuanyuan Zhang, Ying Liu, Jing Xu, Justina Ucheojor Onwuka, Yupeng Liu, Binbin Cui and Yashuang Zhao

According to its incidence patterns, colorectal cancer (CRC) tends to occur more frequently in males than in females, and the evidence shows that CRC is a hormone-related tumor. These findings indicate that androgen receptor (AR) gene methylation might be important for the regulation of the CRC risk in the different sexes. We used a case–control study to investigate the association between AR methylation in peripheral blood (PBL) and CRC risk. A cohort study was conducted to analyze the effect of AR methylation levels in both PBL and tissue on the prognosis of CRC. AR methylation levels were detected using methylation-sensitive high-resolution melting (MS-HRM). The results indicate that the hypomethylation of AR was significantly associated with the risk of CRC (OR = 1.869, 95% CI: 1.629–2.141, P < 0.001), and the results remained similar after adjusting for the propensity score (PS) (OR = 1.344, 95% CI: 1.147–1.575, P < 0.001) and PS matching (OR = 1.138, 95% CI: 1.000–1.292 P = 0.049). The hypomethylation of AR was significantly associated with CRC in males (OR = 2.309, 95% CI: 1.200–4.245; P = 0.012) but not females (OR = 1.000, 95% CI: 0.567–1.765; P = 0.999). The methylation status of AR in PBL and tissue does not seem to be associated with prognosis in colorectal cancer (OR = 1.425, 95% CI: 0.895–2.269, P = 0.135; OR = 0.930, 95% CI: 0.674–1.285, P = 0.661). We conclude that AR hypomethylation in PBL is associated with a high risk of CRC and may serve as a biomarker. Further studies involving large sample sizes are needed to validate the results of this study.

Open access

Lena-Maria Levin, Henry Volzke, Markus M Lerch, Jens-Peter Kühn, Matthias Nauck, Nele Friedrich and Stephanie Zylla

Objective: Chemerin and adiponectin are adipokines assumed to be involved in the development of metabolic syndrome-related phenotypes like hepatic steatosis. We aimed to evaluate the associations of circulating chemerin and adiponectin concentrations with liver enzymes, liver fat content, and hepatic steatosis in the general population.

Methods: Data of 3951 subjects from the population-based Study of Health in Pomerania (SHIP-TREND) were used. Hepatic steatosis was assumed when either a hyperechogenic liver (assessed via ultrasound) or a magnetic resonance imaging (MRI)-quantified liver fat content >5% was present. Adjusted sex-specific quantile and logistic regression models were applied to analyse the associations of chemerin and adiponectin with liver enzymes, liver fat content, and hepatic steatosis.

Results: The observed associations of chemerin and adiponectin with liver enzymes were very divergent depending on sex, fasting status, and the specific enzyme. More consistent results were seen in the analyses of these adipokines in relation to MRI-quantified liver fat content. Here, we observed inverse associations to adiponectin in both sexes as well as a positive (men) or U-shaped (women) association to chemerin. Similarly, the MRI-based definition of hepatic steatosis revealed strongly consistent results: in both sexes high chemerin concentrations were associated with higher odds of hepatic steatosis whereas high adiponectin concentrations were associated with lower odds.

Conclusion: Our results suggest a role of these adipokines in the pathogenesis of hepatic steatosis independent of metabolic or inflammatory disorders. However, experimental studies are needed to further clarify the underlying mechanisms and the inter-play between adipokine concentrations and hepatic steatosis.

Open access

Simon Schimmack, Yongchao Yang, Klaus Felix, Markus Herbst, Yixiong Li, Miriam Schenk, Frank Bergmann, Thilo Hackert and Oliver Strobel

Objective

Elevated pre-operative C-reactive protein (CRP) serum values have been reported to be associated with poor overall survival for patients with pancreatic neuroendocrine neoplasms (pNEN). The aim of this study was to identify mechanisms linking CRP to poor prognosis in pNEN.

Methods

The malignant properties of pNENs were investigated using the human pNEN cell-lines BON1 and QGP1 exposed to CRP or IL-6. Analyses were performed by ELISA, Western blot, flow cytometry and immunocytochemistry as well as invasion and proliferation assays. To compare cytokine profiles and CRP levels, 76 serum samples of pNEN patients were analyzed using Luminex technology. In parallel, the expression of CRP and growth signaling pathway proteins was assessed on cell lines and paraffin-embedded primary pNEN.

Results

In BON1 and QGP1 cells, inflammation (exposure to IL-6) significantly upregulated CRP expression and secretion as well as migratory properties. CRP stimulation of BON1 cells increased IL-6 secretion and invasion. This was accompanied by activation/phosphorylation of the ERK, AKT and/or STAT3 pathways. Although known CRP receptors – CD16, CD32 and CD64 – were not detected on BON1 cells, CRP uptake of pNEN cells was shown after CRP exposure. In patients, increased pre-operative CRP levels (≥5 mg/L) were associated with significantly higher serum levels of IL-6 and G-CSF, as well as with an increased CRP expression and ERK/AKT/STAT3 phosphorylation in pNEN tissue.

Conclusion

The malignant properties of pNEN cells can be stimulated by CRP and IL-6 promoting ERK/AKT/STAT pathways activation as well as invasion, thus linking systemic inflammation and poor prognosis.

Open access

Miranda Scharff, Chantal Maria Wiepjes, Maartje Klaver, Thomas Schreiner, Guy T’Sjoen and Martin den Heijer

Objective

Gender-affirming hormonal treatment (HT) in trans people changes physical appearance. Muscle mass and strength are important aspects of physical appearance, but few data exist on the effect of HT on grip strength and muscle mass. This study aimed to investigate the change in grip strength in trans people during the first year of HT and to study the possible determinants of this change and the associations between changes in grip strength, lean body mass and bone mineral density (BMD).

Design and methods

A multicenter, prospective study was performed, including 249 transwomen and 278 transmen. Grip strength, lean body mass and BMD were measured at baseline and after 1 year.

Results

After 1 year of HT, grip strength decreased with −1.8 kg (95% CI −2.6; −1.0) in transwomen and increased with +6.1 kg (95% CI +5.5; +6.7) in transmen. No differences in grip strength change was found between age groups, BMI groups, hormonal administration routes or hormone concentrations. In transmen, increase in grip strength was associated with increase in lean body mass (per kg increase in grip strength: +0.010 kg, 95% CI +0.003; +0.017), while this was not found in transwomen (per kg increase in grip strength: +0.004 kg, 95% CI −0.000; +0.009). Change in grip strength was not associated with change in BMD in transwomen and transmen.

Conclusions

After 1 year of HT, grip strength decreased in transwomen, and increased in transmen. In transmen only, change in grip strength was associated with change in lean body mass.

Open access

Chiara Mele, Maria Teresa Samà, Alessandro Angelo Bisoffi, Marina Caputo, Valentina Bullara, Stefania Mai, Gillian Elisabeth Walker, Flavia Prodam, Paolo Marzullo, Gianluca Aimaretti and Loredana Pagano

The associative link relating insulin resistance (IR) and adipokines to the occurrence and phenotype of differentiated thyroid cancer (DTC) is unknown. The aim of this study was to evaluate the relationship between IR and adipokines in DTC patients, as compared with carriers of benign thyroid diseases (BTD) and healthy controls. This observational study enrolled 77 subjects phenotyped as DTC (N = 30), BTD (N = 27) and healthy subjects (N = 20). Each subject underwent preoperative analysis of anthropometric parameters, thyroid function and autoimmunity, insulin resistance (HOMA-IR) and levels of unacylated (UAG) and acylated ghrelin (AG), obestatin, leptin and adiponectin. Multivariate regression models were used to test the predictive role of metabolic correlates on thyroid phenotypes and DTC extension. The three groups showed similar age, gender distribution, smoking habit, BMI and thyroid parameters. Obestatin was significantly higher in DTC group compared to BTD (P < 0.05) and control subjects (P < 0.0001). DTC and BTD groups showed higher levels of UAG (P < 0.01) and AG (P < 0.05). Leptin levels were comparable between groups, whereas adiponectin levels were lower in DTC compared to BTD group (P < 0.0001) and controls (P < 0.01). In parallel, HOMA-IR was higher in DTC than BTD (P < 0.05) and control group (P < 0.01). Stepwise multivariable regression analysis showed that obestatin and UAG were independent predictors of DTC (P = 0.01 for both). In an analysis restricted to the DTC group, obestatin levels were associated with the absence of lymph node metastases (P < 0.05). Our results highlight a potential association between metabolic setting, circulating adipokines and thyroid cancer phenotype.