GnRH receptor mediates lipid storage in female adipocytes via AMPK pathway.

Objective: Due to high levels of serum gonadotropin-releasing hormone (GnRH), perimenopausal or menopausal women, girls with central precocious puberty, women of polycystic ovary syndrome, and females receiving long-term GnRH agonist (GnRHa) treatment are at substantially higher risk of developing obesity. However, it remains poorly understood how GnRH affects body weight. Here, we explored whether the gonadotropin-releasing hormone receptor (GnRHR) was expressed in adipocytes and how GnRHR mediated lipid accumulation and the development of obesity. Methods: The samples were from 18 patients with benign tumors operated between 01/2018 and 06/2018 at the Women's Hospital School of Medicine Zhejiang University. Immunofluorescence, Western Blotting, and RT-PCR were used to detect whether the GnRH receptor was expressed in the specimens and human preadipocytes-subcutaneous (HPA-s). The GnRH receptor agonist diphereline with different concentrations was used to stimulate the HPA-s cells for 24, 48, and CCK-8 was used to detect cell proliferation. Oil red-O staining was used to detect lipid droplets in mature adipocytes. The phosphorylation of AMPK-Ser485/Thr172 was detected by Western Blotting. Results: GnRH receptor was expressed in all 18 human subcutaneous adipose tissue specimens. Cultured HPA-s expressed the GnRH receptor, and the expression increased during the process of cell maturation. The GnRH receptor agonist diphereline can stimulate the proliferation of HPA-s cells, which can advance the earliest occurrence of lipid droplets in HPA-s cells and the occurrence of lipid droplets in 50% cells by 1-2 days. Diphereline can stimulate the increase in the number of lipid droplets in mature adipocytes. The phosphorylation level of AMPK-Ser485/Thr172 in mature adipocytes was decreased by diphereline. Conclusion: The GnRH receptor was expressed in adipocytes. As adipocytes mature, GnRH receptor expression gradually increased. GnRHa stimulates the proliferation of HPA-s, promotes adipocyte maturation, increases the formation of lipid droplets in mature adipocytes, and inhibits the activation of the AMPK pathway in adipocytes. Our findings may elucidate the mechanism of obesity in these female populations and provide some evidence on how GnRH contributes to obesity. Additionally, these results provide theoretical support for further research on the mechanisms of obesity, thus enhancing our understanding of the functional diversity of GnRH and establishing a new theoretical basis for the impact of GnRH on metabolism.

Minimally-invasive management of intramural ectopic pregnancy: an eight-case series and literature review.

OBJECTIVE: Intramural pregnancy (IMP) is a rare type of ectopic pregnancy and potentially fatal. Early diagnosis and management of IMP are important to preserve patient fertility. Here, we describe the use of minimally-invasive surgery for early IMP. STUDY DESIGN: We retrospectively analyzed the clinical data of eight patients with IMP treated at our center (January 2010 to December 2018) and reviewed the literature describing minimally-invasive treatment of IMP. RESULTS: All eight patients had at least one risk factor for IMP. Two cases were confirmed by ultrasound, but ectopic pregnancy or gestational trophoblastic disease were initially suspected in the other cases. Surgery (laparoscopic in three patients, hysteroscopic in one patient, and laparoscopic combined with hysteroscopic in four patients) was successful in all cases, and all patients recovered well without complications. The literature review identified 14 articles describing 17 cases of IMP managed with minimally-invasive surgery. Laparoscopic surgery was used successfully as a sole treatment in 10 cases and after failure of hysteroscopic surgery in six cases. Only one case was treated with a combination of hysteroscopic surgery and methotrexate. Interestingly, one case at our center presented with a sinus connecting the gestational sac and uterine cavity and was treated successfully using hysteroscopic surgery during early pregnancy. CONCLUSIONS: Laparoscopic surgery is a feasible management option for most cases of early IMP. Hysteroscopic surgery may be appropriate for cases where a sinus connects the gestational sac with the uterine cavity or when cornual ectopic pregnancy needs to be excluded.

LncRNA snaR upregulates GRB2-associated binding protein 2 and promotes proliferation of ovarian carcinoma cells.

BACKGROUND: The functionality of lncRNA snaR has only been characterized in breast cancer and colon cancer. The aim of the current study is to explore the involvement of lncRNA snaR in ovarian carcinoma (OC). MATERIALS AND METHODS: Expression of lncRNA snaR and GRB2-associated binding protein 2 (GAB2) in plasma of both patients with OC and healthy females was detected by qRT-PCR. Application value of plasma lncRNA snaR in the diagnosis of OC was evaluated by ROC analysis. Correlation between plasma lncRNA snaR and GAB2 was analyzed by Pearson correlation coefficient. LncRNA snaR and GAB2 expression vectors as well as GAB2 siRNA were transfected into cells of human OC cell lines, and the effect on lncRNA snaR expression, GAB2 expression and cell proliferation was detected by qRT-PCR, western blot and CCK-8 assay. RESULTS: It was observed that plasma levels of lncRNA snaR and GAB2 were significantly higher in OC patients than those in healthy controls. In effect, high levels of plasma lncRNA snaR and GAB2 distinguished OC patients from healthy controls. Plasma lncRNA snaR and GAB2 were positively correlated in OC patients but not in healthy controls. LncRNA snaR overexpression promoted cancer cell proliferation and upregulated GAB2 expression. CONCLUSIONS: GAB2 overexpression also promoted cancer cell proliferation but showed no significant effects on lncRNA snaR expression, while GAB2 siRNA silencing significantly attenuated the enhancing effects of lncRNA snaR overexpression on cancer cell proliferation. LncRNA snaR may promote proliferation of ovarian carcinoma cells by upregulating GAB2 expression.

The role of atorvastatin in suppressing tumor growth of uterine fibroids.

BACKGROUND: Medical therapeutic options remain quite limited for uterine fibroids treatment. Statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, have anti-tumoral effects on multiple cancer types, however, little is known about their effects on uterine fibroids. METHODS: Initially, we conducted a retrospective study of 120 patients with uterine fibroids and hyperlipidemia from the Second Affiliated Hospital of Wenzhou Medical University. Then, we evaluated the effect of atorvastatin on proliferation and apoptosis both in immortalized uterine fibroids cells and primary uterine fibroids cells. Furthermore, the molecular mechanism by which atorvastatin suppressed uterine fibroids cell growth was explored. RESULTS: Our results showed that atorvastatin use for 1 or 2 years significantly suppressed growth of uterine fibroids. Atorvastatin inhibited the proliferation of immortalized and primary uterine fibroids cells in a dose and time-dependent manner and stimulated apoptosis of uterine fibroids cells by inducing caspase-3 activation, up-regulating Bim and down-regulating Bcl-2. Additionally, atorvastatin treatment suppressed phosphorylation of ERK1/2 and JNK. Furthermore, GGPP, a downstream lipid isoprenoid intermediate, significantly rescued the effect of atorvastatin. CONCLUSIONS: These results suggest that atorvastatin exerts anti-tumoral effects on uterine fibroids through inhibition of cell proliferation and induction of apoptosis in HMG-CoA-dependent pathway. Our results provide the first clinical and preclinical data on the use of atorvastatin as a promising nonsurgical treatment option for uterine fibroids.

Correlation between estrogen receptor expression and prognosis in epithelial ovarian cancer: a meta-analysis.

OBJECTIVE: Accumulated studies have investigated the prognostic significance of estrogen receptor expression in epithelial ovarian cancer, but results remain controversial. The aim of this study was to perform a meta-analysis to clarify the prognostic value of estrogen receptor expression in epithelial ovarian cancer. METHODS: A systematic search was performed in PUBMED, EMBASE, and COCHRANE databases to identify relevant studies up to December 2016. The pooled hazard rates (HR) with 95% confidence intervals (CIs) for overall survival and time to tumor progression were calculated and then weighted and pooled in this meta-analysis with a random-effect model. RESULTS: Thirty-five studies with a total of 5824 patients were included. In brief, the expression of estrogen receptor was associated with an improved overall survival (HR = 0.86, 95% CI = 0.76-0.97), whereas there was no significant difference between estrogen receptor and time to tumor progression among epithelial ovarian cancer patients. Subgroup analysis revealed that estrogen receptor expression was significantly correlated with overall survival in different subgroups, such as in unclassified epithelial ovarian cancer (HR= 0.80, 95% CI = 0.66-0.95), studies using immunohistochemistry detection method (HR= 0.85, 95% CI = 0.73-1.00), European population (HR= 0.75, 95% CI = 0.60-0.94) and estrogen receptor α subtype (HR= 0.78, 95% CI = 0.62-0.98). CONCLUSIONS: Estrogen receptor, especially estrogen receptor α, was associated with an improved overall survival in epithelial ovarian cancer. Estrogen receptor expression may be a promising prognostic factor in epithelial ovarian cancer patients.

Factors related to completeness of medical abortion with mifepristone and misoprostol.

BACKGROUND: Medical abortion that occurs in early pregnancy is generally safe and successful, but incomplete medical abortion can result in complications. This study aimed to examine factors related to completeness of medical abortion with mifepristone and misoprostol, and then to provide a new direction for research into establishing complete abortion with mifepristone and misoprostol. METHODS: Sixty-three patients with early pregnancy requesting medical abortion with mifepristone and misoprostol were selected. Immunohistochemistry was used to detect the expression and location of progesterone receptor, estrogen receptor, insulin-like growth factor-1, and vascular endothelial growth factor in chorionic villi among these women. Reverse transcriptase polymerase chain reaction was then used to determine the expression of insulin-like growth factor-1 and vascular endothelial growth factor mRNA. RESULTS: According to the outcome of medical abortion, the women were divided into either the incomplete medical abortion group (n=34) or the complete medical abortion group (n=29). Immunohistochemical analysis showed that progesterone receptor and estrogen receptor protein expression was not detected in chorionic villi in the two groups. However, compared with the complete abortion group, there was a marked decrease in the expression of insulin-like growth factor-1 and a significant increase in the expression of vascular endothelial growth factor (p<0.05) in the incomplete abortion group. There was no significant difference in mRNA expression between the incomplete and complete abortion groups. CONCLUSION: The expression of insulin-like growth factor 1 protein and vascular endothelial growth factor protein in chorionic villi may be related to the outcome of medical abortion with mifepristone and misoprostol.

Linking expression of aquaporin 3 to activation of JNK pathway.

Aquaporin 3 (AQP3) has been shown to be low in the amnion and chorion tissues of patients with oligohydramnios and that S. miltiorrhiza, a Chinese herbal medicine, results in increased AQP3 in human amniotic epithelial cells (hAECs). Here, we provide evidence for the involvement of the JNK pathway in AQP3 regulation in isolated oligohydramnios tissues in vitro, in hAECs derived from normal amniotic fluid and fluid from patients with isolated oligohydramnios. Phosphorylation of JNK was suppressed by pretreatment of cells with JNK-specific inhibitor (SP600125) and was up-regulated by S. miltiorrhiza; S. miltiorrhiza combined with SP600125 prevented SP600125-induced down-regulation of phospho-JNK both in normal amniotic fluid volume and in isolated oligohydramnios. In isolated oligohydramnios, AQP3 expression was significantly suppressed by SP600125 in a concentration- and time-dependent mannner, while its expression was up-regulated by S. miltiorrhiza. S. miltiorrhiza combined with SP600125 inhibited the increased expression of AQP3 relative to the S. miltiorrhiza treated group. Together, the data suggest that c-jun N-terminal kinase (JNK) pathway unerlies the regulation of AQP3 by S. miltiorrhiza amnion and chorion tissues.

The Benefits and Side Effects of Bevacizumab for the Treatment of Recurrent Ovarian Cancer.

BACKGROUND: Ovarian cancer is the leading cause of deaths attributable to gynecologic malignancies. Late diagnosis and a high tendency of metastasis and drug resistance often lead to recurrence and poor outcomes. Anti-angiogenesis is considered a promising therapeutic strategy for recurrent ovarian cancers. Anti-VEGF body, bevacizumab, is an angiogenesis inhibitor with demonstrated activity and tolerable toxicity. OBJECTIVE: To elucidate the benefits and side effects of bevacizumab for the therapy of recurrent ovarian cancer. METHODS: Reviewed the results of published clinical trials. RESULTS: Recent Phase II studies indicated that bevacizumab monotherapy or in combination with conventional or other anti-angiogenic chemotherapy reagents could be effective for recurrent (platinum- sensitive and -resistant) ovarian cancers. Additionally, two phase III randomized trials reached similar conclusions that in either platinum-sensitive or -resistant ovarian cancers, adding bevacizumab to chemotherapy can improve progression-free survival. Despite the general recognition of bevacizumab as a well-tolerated drug in recurrent ovarian cancer patients, oncologists have become aware of the significant risks associated with gastrointestinal perforation. CONCLUSION: Bevacizumab used alone or combined with other chemotherapy reagents is efficacious and tolerable in the treatment of recurrent ovarian cancer.

PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer.

Pyruvate kinase M2 (PKM2) is a key driver of aerobic glycolysis in cancer cells and has been shown to be up-regulated by mTOR in vitro. Our previous proteomic profiling studies showed that PKM2 was significantly upregulated in cervical cancer tissues after treatment with neoadjuvant chemotherapy (NACT). Whether PKM2 expression predicts cisplatin-based NACT sensitivity and is mTOR dependent in cervical cancer patients remains unclear. Using paired tumor samples (pre- and post-chemotherapy) from 36 cervical cancer patients, we examined mTOR, HIF-1α, c-Myc, and PKM2 expression in cervical cancer samples and investigated the response to cisplatin-based NACT. In addition, we established PKM2 suppressed cervical cancer cell lines and evaluated their sensitivity to cisplatin in vitro. We found that the mTOR/HIF-1α/c-Myc/PKM2 signaling pathway was significantly downregulated in post-chemotherapy cervical cancer tissues. High levels of mTOR, HIF-1α, c-Myc, and PKM2 were associated with a positive chemotherapy response in cervical cancer patients treated with cisplatin-based NACT. In vitro, PKM2 knockdown desensitized cervical cancer cells to cisplatin. Moreover, PKM2 had complex interactions with mTOR pathways. mTOR, HIF1α, c-Myc, and PKM2 expression in cervical cancer may serve as predictive biomarkers to cisplatin-based chemotherapy. PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer.

Comparison of polyvinyl alcohol and tris-acryl gelatin microsphere materials in embolization for symptomatic leiomyomas: a systematic review.

OBJECTIVE: Use systematic reviews and meta-analyses to assess the effect of polyvinyl alcohol and tris-acryl gelatin microsphere materials in leiomyoma embolization for symptomatic leiomyomas. MATERIAL AND METHODS: We included randomised controlled studies published before January 2015 comparing polyvinyl alcohol and tris-acryl gelatin microsphere materials in uterine leiomyoma embolization for women with symptomatic leiomyomas. The main outcome measures included change of overall quality of life, change of overall symptom severity, changes of uterine and leiomyoma volumes, leiomyoma infarction rate, treatment failure and complications. RESULTS: A total of six randomized controlled studies from 335 studies accounting for 351 women with leiomyomas were identified in this meta-analysis. Compared to polyvinyl alcohol, tris-acryl gelatin microsphere showed a significant benefit in improving the overall quality of life and in reducing uterine volume at three and six months, in reducing overall symptom severity at 6 and 12 months, and furthermore in reducing treatment failure. In addition, tris-acryl gelatin microsphere could significantly reduce leiomyoma volume and decrease <90% complete leiomyoma infarction rate at three months. There were no differences in pain severity, other post-procedural symptoms or medication use in the two groups. CONCLUSIONS: A better effect of tris-acryl gelatin microsphere in leiomyoma embolization for patients with symptomatic leiomyoma.

Molecular mechanisms of cisplatin resistance in cervical cancer.

Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%-20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer.

Chlamydia Trachomatis Infection-Associated Risk of Cervical Cancer: A Meta-Analysis.

As whether Chlamydia trachomatis infection increases the risk of cervical cancer is controversial in the literature, we performed a meta-analysis.Based on a comprehensive search of publications in the Medline, Cochrane, and EMBASE databases, we identified and extracted data from all relevant articles examining C. trachomatis infection and the risk of cervical cancer. The quality of each included study was assessed according to the 9-star Newcastle-Ottawa scale. The strength of association between the C. trachomatis and risk of cervical cancer was estimated by odds ratio (OR) and 95% confidence intervals (CIs). This review was registered at PROSPERO with registration No. CRD42014015672. A total of 22 studies with 4291 cervical cancer cases and 7628 controls were identified. Overall, C. trachomatis was significantly linked to increased cervical cancer risk in prospective studies (OR = 2.21, 95% CI: 1.88-2.61, P < 0.001), as well as in retrospective studies (OR = 2.19, 95% CI: 1.74-2.74, P < 0.001). Additionally, with a multivariate logistic regression analysis adjusted for HPV and age, C. trachomatis infection was identified as an independent predictor of cervical cancer in 11 studies (OR = 1.76, 95% CI: 1.03-3.01, P = 0.04). Coinfection of human papilloma virus and C. trachomatis has a higher risk of cervical cancer (OR = 4.03, 95% CI: 3.15-5.16, P < 0.001). A subgroup analysis based on histological type indicated an elevated risk for both squamous cell carcinoma (OR = 2.21, 95% CI: 2.00-2.45, P < 0.001), and adenocarcinoma (OR = 1.61, 95% CI: 1.21-2.15, P = 0.001), in associated with C. trachomatis. Subgroup analysis by where C. trachomatis infection was detected showed a significantly higher risk of cervical cancer associated with C. trachomatis infection detected in serum (OR = 2.20, 95% CI: 2.01-2.42, P < 0.001), cervical tissue blocks (OR = 2.88, 95% CI: 1.21-6.83, P = 0.02), and cervical secretion (OR = 2.71, 95% CI: 1.41-5.20, P = 0.003), especially in serum with no obvious heterogeneity.In conclusion, our novel data demonstrate that individuals infected with C. trachomatis have a higher risk of cervical cancer. Therefore, it is necessary to expand C. trachomatis infection screening and treat women with C. trachomatis promptly, particularly those with human papilloma virus infections. This approach will not only protect against pelvic inflammatory disease and infertility, but may also prevent cervical cancer.

Expression and function of peroxiredoxins in gynecological malignancies.

A large family of peroxiredoxin proteins plays essential roles in the regulation of multiple redox-sensitive cellular activities related to cell signaling, cell proliferation and apoptosis. The involvement of these proteins in protecting cells from oxidative damage, induced by reactive oxygen species, points to their potential role in human cancers. According to some studies, the peroxiredoxin proteins in gynecological malignancies, promote tumors development and progression, whereas others indicate that peroxiredoxin proteins function as onco-suppressors in these cancers. Here, we review the utilization of peroxiredoxin proteins as novel biomarkers for screening and early diagnosis of gynecological malignancies, and as the specific therapy targets and prognostic factors as well.

Down-regulation and gene hypermethylation of the 14-3-3 gamma in uterine leiomyoma.

We demonstrated that the expression of 14-3-3 gamma was lower in uterine leiomyomas compared to the adjacent normal myometrium. Here, we show that 14-3-3 gamma promoter is methylated more in leiomyomas than myometrium. The level of 14-3-3 gamma protein in leiomyomas did not change in respect to age, size, location, or the type of leiomyoma. ER-alpha, ER-beta, and PR proteins were also higher in leiomyomas and the level of these proteins negatively correlated with the level of 14-3-3 gamma protein. These results suggest that the hypermethylation of the 14-3-3 gene promoter accounts for the decreased 14-3-3 gamma in leiomyomas and that such a low level of expression may be involved in the pathogenesis of leiomyomas.

Transforming growth factor-ß1 in carcinogenesis, progression, and therapy in cervical cancer.

Transforming growth factor ß1 (TGF-ß1) is a multifunctional cytokine that plays important roles in cervical tumor formation, invasion, progression, and metastasis. TGF-ß1 functions as a tumor inhibitor in precancerous lesions and early stage cancers of cervix whereas as a tumor promoter in later stage. This switch from a tumor inhibitor to a tumor promoter might be due to various alterations in TGF-ß signaling pathway, such as mutations or loss of expression of TGF-ß receptors and SMAD proteins. Additionally, the oncoproteins of human papillomaviruses have been shown to stimulate TGF-ß1 expression, which in turn suppresses host immune surveillance. Thus, in addition to driving tumor cell migration and metastasis, TGF-ß1 is believed to play a key role in promoting human papillomavirus infection by weakening host immune defense. In this article, we will discuss the role of TGF-ß1 in the expression, carcinogenesis, progression, and therapy in cervical cancers. A better understanding of this cytokine in cervical carcinogenesis is essential for critical evaluation of this cytokine as a potential prognostic marker and therapeutic target.

An Herbal Galactagogue Mixture Increases Milk Production and Aquaporin Protein Expression in the Mammary Glands of Lactating Rats.

Background. Herbal galactagogues have been increasingly used to treat postpartum hypogalactia. The mechanism of action of herbal galactagogues remains unclear. The purpose of this study was to investigate the effect of an herbal galactagogue mixture on milk production and aquaporin (AQP) expression in lactating rats. Methods. Thirty female Sprague Dawley rats were randomized into virgin, lactating + H2O, and lactating + galactagogue groups (n = 10 per group). Lactating rats were administered the decoction of an herbal galactagogue mixture by oral gavage or the same amount of distilled water. Results. The herbal decoction significantly increased milk production in lactating rats (P < 0.05). Both immunohistochemical staining and western blot showed that protein levels of AQP-3 and AQP-5 were significantly increased during lactation compared with virgin stage and the herbal decoction further elevated their expression (P < 0.05). AQP-1 was predominantly expressed in the capillaries whereas AQP-3 and AQP-5 were mainly detected in the epithelial cells and ducts of the mammary glands. Conclusion. The expression of AQPs in the mammary glands of rats was developmentally regulated. Herbal galactagogues might have increased milk secretion by regulating the expression and function of AQPs in the mammary glands.

Effect of coffee consumption on the risk of gastric cancer: a systematic review and meta-analysis of prospective cohort studies.

BACKGROUND AND OBJECTIVES: Results from observational epidemiologic studies on the relationship between coffee consumption and gastric cancer are inconsistent and inconclusive. To assess the association between coffee consumption and the risk of gastric cancer, we summarized evidence from prospective cohort studies. METHODS: Relevant studies were retrieved through computer searches (PubMed, EmBase and the Cochrane Library) and a review of references up to December 2014. The quality of the included studies was evaluated by Newcastle-Ottawa quality assessment scale. We used a meta-analytic approach to estimate overall hazard ratios (HRs) and 95% confidence intervals (CIs) for regular coffee drinkers versus individuals who seldom drank coffee. Sensitivity analysis and subgroup analysis were performed to assess the reliability of our results. A dose-response analysis was performed to assess the risk of gastric cancer based on the level of coffee consumption. RESULTS: Nine prospective cohort studies involving 1,250,825 participants and 3027 gastric cancer cases were included in this meta-analysis. The pooled HR of gastric cancer for the study-specific regularly versus seldom coffee drinking categories was 1.05 (95% CI, 0.88 to 1.25) with significant heterogeneity across studies (I(2) = 74.0%, P = 0.000). After the sensitivity analysis, three studies were deleted; however the association remained insignificant (HR, 0.99; 95% CI, 0.91 to 1.08). Subgroup analysis by anatomic location showed a risk for coffee consumption associated with cardia cancer (HR, 1.23; 95% CI, 1.04 to 1.45; heterogeneity, I(2) = 36.4, P = 0.207). In the dose-response analysis, there was no significant association between coffee intake (in cups) and the risk of gastric cancer (P for linearity trend and non-linearity > 0.05). CONCLUSION: Our meta-analysis demonstrated that coffee consumption was not associated with overall gastric cancer risk; however, coffee consumption may be a risk factor for gastric cardia cancer.