[Retracted] MicroRNA­202 inhibits endometrial stromal cell migration and invasion by suppressing the K­Ras/Raf1/MEK/ERK signaling pathway.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell invasion assay data shown in Figs. 2C and 4B were strikingly similar to data appearing in different form in a paper by different authors at a different research institute that had already been submitted for publication. Owing to the fact that the contentious data in the above article had already been submitted for publication prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 46: 2078­2088, 2020; DOI: 10.3892/ijmm.2020.4749].

Prognostic factors and clinic-pathologic characteristics of ovarian tumor with different histologic subtypes-a SEER database population study of 41,376 cases.

Background: Ovarian cancer is considered the leading cause of cancer-related deaths among all gynecological malignancies and a significant reason for mortality in women. This cohort study aimed to explore the survival trends of malignant ovarian tumors (MOT), cancer antigen 125 (CA125) level, and clinicopathological prognostic factors of MOT by histological subtype. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, a total of 41,411 MOT cases diagnosed between January 2005 and December 2014 were extracted. According to the histological classification of MOT, four categories were included: epithelial ovarian carcinoma (EOC), malignant ovarian germ cell tumors (MOGCTs), malignant ovarian sex cord-stromal tumors (MOSCSTs) and ovarian neuroendocrine tumors (ONTs). We analyzed disease-specific survival (DS) and overall survival (OS) among the four categories, and their histological subtypes. Kaplan-Meier method was used to estimate survival curves, and log-rank test was used to evaluate differences between curves. Univariate and multivariate Cox proportional hazards models were applied to evaluate the prognostic impact of MOT. Results: Significant predictors related to improved OS were younger age, low grade, early FIGO stage and localized SEER stage, while positive/elevated CA125 level was a risk factor. For MOGCT and MOSCST, 3-, 5- and 10-year DS rate estimates were all >80%, followed by ONT around 70%. Malignant epithelial cancer showed low DS rate at 3-year (70.7%), 5-year (58.7%), and 10-year (47.3%). Conclusions: EOC patients had the worst outcome, whereas MOGCT cases had the most favorable survival. Positive/elevated CA125 level led to poor prognosis. Furthermore, younger age, low grade, early FIGO stage and localized SEER stage were significant predictors for improved OS.

Adenoid cystic carcinoma of the Bartholin's gland is easily misdiagnosed: A case report and literature review.

RATIONALE: Adenoid cystic carcinoma (ACC) often occurs in the major and minor salivary glands and other sites containing secretory glands, while ACC of the Bartholin's gland (BG-ACC) in the vulva is rare and easily misdiagnosed. PATIENT CONCERNS: A 58-year-old female was referred to our hospital for further valuation of a mass occurring on the left side of her vulva. In the other hospital, the beginning of the period, local ultrasound showed a vulva mass, which was suspected to be a Bartholin's gland cyst. Mixed neoplasms were considered in some biopsies. When transferred to our hospital, virtuous tumors were considered by ultrasound and magnetic resonance imaging. Pathology initially considered benign hyperplastic active tumor or borderline tumor. DIAGNOSES: Histological, immunochemical, and molecular tests confirmed a diagnosis of BG-ACC, negative surgical margin, without lymphatic metastasis. INTERVENTIONS: Extended excision of the mass at left labia majora plus left inguinal lymph node dissection was performed. OUTCOMES: The patient received surgery therapy, no recurrence was observed during a 18-month follow-up period. LESSONS: Due to its lack of specific characteristics in clinical, ultrasound and imaging, it is easy to be misdiagnosed, Due to its rarity and nonspecific clinical, radiologic and ultrasonographic manifestations, BG-ACC can be easily misdiagnosed. And its pathomorphological features overlap with other benign and malignant tumors occurring at vulva, BG-ACC can be easily misdiagnosed, and diagnosis by puncture biopsy is extremely difficult. Use of paraffin sections to identify tumor growth characteristics, combined with immunohistochemical findings, is the key to the diagnosis of ACC. In rare sites, MYB gene split are helpful in making a definite diagnosis.

Clinicopathological Features, Prognostic Factors, Survival Trends, and Treatment of Malignant Ovarian Germ Cell Tumors: A SEER Database Analysis.

OBJECTIVE: The aim of this study was to investigate the clinicopathological prognostic factors of malignant ovarian germ cell tumors (MOGCT) and evaluate the survival trends of MOGCT by histotype. METHODS: We extracted data on 1,963 MOGCT cases diagnosed between 2000 and 2014 from the Surveillance, Epidemiology, and End Results (SEER) database and the histological classification of MOGCT, including 5 categories: dysgerminoma, embryonal carcinoma (EC), yolk sac tumor, malignant teratoma, and mixed germ cell tumor. We examined overall and disease-specific survival of the 5 histological types. Kaplan-Meier and Cox proportional hazards regression models were used to estimate survival curves and prognostic factors. We also estimated survival curves of MOGCT according to different treatments. RESULTS: There was a significant difference in prognosis among different histological classifications. Age, histotype, grade, SEER stage, and surgery were independent prognostic factors for survival of patients with MOGCT. For all histotypes, 1-, 3-, and 5-year survival rate estimates were >85%, except for EC, which had the worst outcomes at 1 year (55.6%), 3 years (44.4%), and 5 years (33.3%). In the distant SEER stage, both chemotherapy and surgery were associated with improved survival outcomes compared with surgery- and chemotherapy-only groups. CONCLUSIONS: Dysgerminoma patients had the most favorable outcomes, whereas EC patients had the worst survival. A young age, low grade, and surgery were all significant predictors for improved survival. In contrast, a distant SEER stage was a risk factor for poor survival. Chemotherapy combined with surgery contributed to longer survival times of patients with MOGCT in the distant SEER stage.

MicroRNA­202 inhibits endometrial stromal cell migration and invasion by suppressing the K­Ras/Raf1/MEK/ERK signaling pathway.

The enhanced migratory ability of endometrial stromal cells (ESCs) is a key factor in the formation of functional endometrium­like tissues outside the uterine cavity during endometriosis (EMS). Although accumulating evidence has suggested the importance of microRNAs (miRNAs) in the pathogenesis of EMS, the role of particular miRNAs in the invasiveness of ESCs remain poorly understood. In the present study, the function of miRNAs in the invasiveness of ESCs, along with the associated underlying mechanism involved, were investigated. Initially, the expression patterns of miRNAs in the ectopic and eutopic endometrium isolated from patients with EMS were analyzed using microarray. MicroRNA­202­5p (miR­202) was selected for further study due to its previously reported suppressive effects on the invasion in various types of cancers. The expression of miR­202 and K­Ras in eutopic and ectopic endometrioma tissues were detected using reverse transcription­quantitative PCR, immunohistochemistry and western blotting. The migration and invasion ability of ESCs was determined using wound healing and Transwell invasion assays, respectively. Compared with that from healthy individuals, miR­202 expression was demonstrated to be lower in the eutopic endometrium from patients with EMS, which was even lower in ectopic endometrium. Functional experiments in primary ESCs revealed that enhanced miR­202 expression suppressed the cell invasion and migration abilities, which was also accompanied with increased E­cadherin and reduced N­cadherin expression in ESCs, suggesting its potentially suppressive role in epithelial­mesenchymal transition. K­Ras is a well­known regulator of the ERK signaling pathway that was shown to be directly targeted and negatively regulated by miR­202. In addition, K­Ras expression was found to be upregulated in the ectopic endometrium, where it correlated negatively with that of miR­202. Knocking down K­Ras expression mimicked the anti­invasive effects of miR­202 overexpression on ESCs, whilst K­Ras overexpression attenuated the inhibitory role of miR­202 overexpression in ESC invasion. The K­Ras/Raf1/MEK/ERK signaling pathway was also blocked by miR­202 overexpression. These findings suggested that miR­202 inhibited ESC migration and invasion by inhibiting the K­Ras/Raf1/MEK/ERK signaling pathway, rendering miR­202 a candidate for being a therapeutic target for EMS.

Higenamine Combined with [6]-Gingerol Suppresses Doxorubicin-Triggered Oxidative Stress and Apoptosis in Cardiomyocytes via Upregulation of PI3K/Akt Pathway.

Sini decoction is a well-known formula of traditional Chinese medicine, which has been used to treat cardiovascular disease for many years. Previously, we demonstrated that Sini decoction prevented doxorubicin-induced heart failure in vivo. However, its active components are still unclear. Thus, we investigated the active components of Sini decoction and their cardioprotective mechanisms in the in vitro neonatal rat cardiomyocytes and H9c2 cell line models of doxorubicin-induced cytotoxicity. Our results demonstrated that treatment with higenamine or [6]-gingerol increased viability of doxorubicine-injured cardiomyocytes. Moreover, combined use of higenamine and [6]-gingerol exerted more profound protective effects than either drug as a single agent, with effects similar to those of dexrazoxane, a clinically approved cardiac protective agent. In addition, we found that treatment with doxorubicin reduced SOD activity, increased ROS generation, enhanced MDA formation, induced release of LDH, and triggered the intrinsic mitochondria-dependent apoptotic pathway in cardiomyocytes, which was inhibited by cotreatment of higenamine and [6]-gingerol. Most importantly, the cytoprotection of higenamine plus [6]-gingerol could be abrogated by LY294002, a PI3K inhibitor. In conclusion, combination of higenamine and [6]-gingerol exerts cardioprotective effect against doxorubicin-induced cardiotoxicity through activating the PI3K/Akt signaling pathway. Higenamine and [6]-gingerol may be the active components of Sini decoction.

Polysaccharide from Fuzi likely protects against starvation-induced cytotoxicity in H9c2 cells by increasing autophagy through activation of the AMPK/mTOR pathway.

There is increasing evidence that starvation induces autophagy, which may be protective during starvation, in an AMPK-dependent manner. Polysaccharides from Fuzi (FPS) reportedly have protective effects on nutrition-limited livers. The present study was designed to determine whether FPS protected H9c2 cells against starvation-induced cytotoxicity using an AMPK/mTOR-dependent mechanism. H9c2 cells were incubated in serum and glucose starvation media for 12 hours to establish a cell injury model. 3-Methyladenine (3MA, an autophagy inhibitor) was used to identify the exact role of autophagy in starvation. Cells were incubated with different FPS concentrations, and the cell injury levels, autophagy activity and AMPK/mTOR phosphorylation were measured. Adenine 9-ß-D-arabinofuranoside (Ara-A, an AMPK inhibitor) and 5-amino-4-imidazole-carboxamide riboside (AICAR, an AMPK activator) were used to identify whether the AMPK/mTOR pathway was involved in FPS-mediated cardioprotection. We demonstrated that starvation decreased cell viability in a time-dependent manner, and 3MA-induced autophagy inhibition aggravated the reduced cell viability. FPS treatment attenuated the cell viability decrement and the starvation-induced decline in the mitochondrial membrane potential (MMP), and autophagy; also, the AMPK/mTOR pathways were activated during treatment. Ara-A treatment abolished the protective effect of FPS, while AICAR treatment had a similar effect to FPS. We conclude that autophagy attenuates starvation-induced cardiomyocyte death, and FPS increases autophagy activity to protect against starvation-induced cytotoxicity in H9c2 cells, likely through AMPK/mTOR pathway activation.

Resveratrol protects HUVECs from oxidized-LDL induced oxidative damage by autophagy upregulation via the AMPK/SIRT1 pathway.

PURPOSE: Resveratrol could induce basal autophagy through the activation of sirtuin. In this study, we investigated the effect of resveratrol on oxidative injury of human umbilical endothelial vein cells (HUVECs) induced by oxidized low-density lipoprotein (ox-LDL) and the role of autophagy in this effect. METHODS: HUVECs were exposed to 100 mg/L ox-LDL for 24 h to cause oxidative injury. The effect of different concentrations of resveratrol on oxidative damage in HUVECs treated with ox-LDL was evaluated by MTT assay and superoxide dismutase (SOD) activity test. The autophagic level in different groups was measured by the protein expression of microtubule-associated protein 1 light chain 3 (LC3) and sequestosome 1 (SQSTM1/P62). Autophagosomes were observed under electron microscope and fluorescence microscope (by MDC staining). The expression of silencing information regulator1 (Sirt1) and AMP activated protein kinaseα1 (AMPK) was investigated by Western blot. Autophagy inhibitor 3-methyladenine (3-MA) and Sirt1 inhibitor 6-Chloro-2,3,4,9-tetrahydro-1H-Carbazole-1-carboxamide (EX527) were used to confirm the role of autophagy in this effect of resveratrol and the pathway involved. RESULTS: Resveratrol reversed the decreases in cell viability (72.9 ± 1.7 % of the control group) and SOD activity (14.37 ± 0.21 U/ml) caused by ox-LDL at 83.4 ± 1.4 % of the control group and 16.41 ± 0.27 U/ml respectively. This effect accompanied by upregulation of autophagy and increased protein expression of Sirt1 and AMPK phosphorylation on threonine 172 (p-AMPK). Both 3-MA and EX527 abolished the protective effect of resveratrol in cell viability, at 80.4 ± 2.7 % and 73.9 ± 1.1 % of the control group respectively. 3-MA inhibited autophagy activation without any change of Sirt1 expression at both the mRNA and protein level. EX527 suppressed the expression of Sirt1 and diminished the upregulation of autophagy. Addition of 3-MA or EX527 could not affect the protein level of p-AMPK. CONCLUSION: Resveratrol protected HUVECs from oxidative damage caused by ox-LDL. This effect was mediated by Sirt1-dependent autophagy via the AMPK/ Sirt1 pathway.

Jiaweisinisan facilitates neurogenesis in the hippocampus after stress damage.

The traditional Chinese medicine Jiaweisinisan has antidepressant effects, and can inhibit hypothalamus-pituitary-adrenal gland axis hyperactivity in stress-induced depression. In this study, rat hippocampal neural precursor cells were cultured in serum-free medium in vitro and a stress damage model was established with 120 µM corticosterone. Cells were treated with 10% (v/v) Jiaweisinisan drug-containing serum and the corticosterone antagonist RU38486. Results of the 3-(4,5-dimethylthiazol-2-yl)-3,5-di-phenytetrazoliumromide assay showed that both Jiaweisinisan drug-containing serum and RU38486 promoted the proliferation of neural precursor cells after corticosterone exposure. Immunofluorescence detection showed that after Jiaweisinisan drug-containing serum and RU38486 treatment, the 5-bromo-2-deoxyuridine/terminal deoxynucleotidyl transferase dUTP nick end labeling ratio in hippocampal neural precursor cells significantly increased, and the apoptotic rates of glial cells reduced, and neuron-like cell differentiation from neural precursor cells significantly increased. Our experimental findings indicate that Jiaweisinisan promotes hippocampal neurogenesis after stress damage.