A Low Dose of Ouabain Alters the Metabolic Profile of Adult Rats Experiencing Intrauterine Growth Restriction in a Sex-Specific Manner.

Intrauterine growth restriction (IUGR) increases the risk of type 2 diabetes mellitus (T2DM) and metabolic diseases. The pancreas of fetuses with IUGR is usually characterized by pancreatic dysplasia and reduced levels of insulin secretion caused by the diminished replication of ß-cells. Previous studies showed that a low dose of ouabain could reduce the apoptosis of embryonic nephric cells during IUGR and partially restore the number of nephrons at birth. The rescued kidneys functioned well and decreased the prevalence of hypertension. Thus, we hypothesized that ouabain could rescue pancreatic development during IUGR and reduce the morbidity of T2DM and metabolic diseases. Maternal malnutrition was used to induce the IUGR model, and then a low dose of ouabain was administered to rats with IUGR during pregnancy. Throughout the experiment, we monitored the pattern of weight increase and evaluated the metabolic parameters in the offspring in different stages. Male, but not female, offspring in the IUGR group presented catch-up growth. Ouabain could benefit the impaired glucose tolerance of male offspring; however, this desirable effect was eliminated by aging. The insulin sensitivity was significantly impaired in male offspring with IUGR, but it was improved by ouabain, even during old age. However, in the female offspring, low birth weight appeared to be a beneficial factor even in old age; administering ouabain exacerbated these favorable effects. Our data suggested that IUGR influenced glucose metabolism in a sex-specific manner and ouabain treatment during pregnancy exerted strongly contrasting effects in male and female rats.

Uterine leiomyoma with fumarate hydratase deficiency: A case report.

RATIONALE: Hereditary leiomyomatosis and renal cell carcinoma is an uncommon autosomal dominant disease caused by mutations in the fumarate hydratase (FH) gene. They usually demonstrated multiple uterine myomas and preformed surgical procedures for myomectomy and/or hysterectomy 10 years earlier than sporadic myomas due to early development. This case report describes a woman with multiple uterine leiomyomas diagnosed with FH deficiency. PATIENT CONCERNS: A 37-year-old woman visited a gynecological clinic for the discovery of uterine leiomyoma for more than 1 year. The size of the largest grew from 42 × 27 × 46 to 98 × 85 × 113 mm in 1 year. She had a history of surgery for breast cancer and thyroid cancer but denied a history of uterine leiomyoma in her family. DIAGNOSIS AND INTERVENTIONS: The patient underwent successful transabdominal hysterectomy. The pathological results showed multiple uterine leiomyomas (partly cellular leiomyomas) with scattered large bizarre giant cells. Immunohistochemistry results demonstrated FH deficiency. OUTCOMES: On follow-up, the patient did not have any complications. She was finally referred to the oncologists and urologists for follow-up. LESSONS: Gynecologists should be aware that early onset uterine leiomyoma presenting as large, multiple, and symptomatic lesion, may be associated with FH deficiency.

SNX10 and PTGDS are associated with the progression and prognosis of cervical squamous cell carcinoma.

BACKGROUND: Cervical cancer (CC) is the primary cause of death in women. This study sought to investigate the potential mechanism and prognostic genes of CC. METHODS: We downloaded four gene expression profiles from GEO. The RRA method was used to integrate and screen differentially expressed genes (DEGs) between CC and normal samples. Functional analysis was performed by clusterprofiler. We built PPI network by Search Tool for the Retrieval of Interacting Genes Database (STRING) and selected hub modules via Molecular COmplex Detection (MCODE). CMap database was used to find molecules with therapeutic potential for CC. The hub genes were validated in GEO datasets, Gene Expession Profiling Interactive Analysis (GEPIA), immunohistochemistry, Cox regression analysis, TCGA methylation analysis and ONCOMINE were carried out. ROC curve analysis and GSEA were also performed to describe the prognostic significance of hub genes. RESULTS: Functional analysis revealed that 147 DEGs were significantly enriched in binding, cell proliferation, transcriptional activity and cell cycle regulation. PPI network screened 30 hub genes, with CDK1 having the strongest connectivity with CC. Cmap showed that apigenin, thioguanine and trichostatin A might be used to treat CC(P < 0.05). Eight genes (APOD, CXCL8, MMP1, MMP3, PLOD2, PTGDS, SNX10 and SPP1) were screened out through GEPIA. Of them, only PTGDS and SNX10 had not appeared in previous studies about CC. The validation in GEO showed that PTGDS showed low expression while SNX10 presented high expression in tumor tissues. Their expression profiles were consistent with the results in immunohistochemistry. ROC curve analysis indicated that the model had a good diagnostic efficiency (AUC = 0.738). GSEA analysis demonstrated that the two genes were correlated with the chemokine signaling pathway (P < 0.05). TCGA methylation analysis showed that patients with lowly-expressed and highly-methylated PTGDS had a worse prognosis than those with highly-expressed and lowly-methylated PTGDS (p = 0.037). Cox regression analysis showed that SNX10 and PTGDS were independent prognostic indicators for OS among CC patients (P = 0.007 and 0.003). CONCLUSIONS: PTGDS and SNX10 showed abnormal expression and methylation in CC. Both genes might have high prognostic value of CC patients.

MicroRNA-132 and microRNA-212 mediate doxorubicin resistance by down-regulating the PTEN-AKT/NF-κB signaling pathway in breast cancer.

Breast cancer is a serious health problem worldwide. Acquisition of multi-drug resistance (MDR) during the treatment of breast cancer is still considered a major clinical obstacle. Despite the biological functions of miRNAs becoming increasingly apparent, the function of miRNAs in regulating drug resistance of breast cancer remains under investigation. Quantitative real-time PCR (qRT-PCR) was used to quantify the expression of miR-132/-212 (miR-132 and miR-212) in doxorubicin (DOX)-resistant and -sensitive breast cancer tumors and cells. The function of miR-132/-212 in drug resistance was investigated in vitro (MTT assay, TUNEL assay, fluorescence, immunohistochemistry, luciferase reporter assay, Western blotting). We found that miR-132/-212 were commonly overexpressed in DOX-resistant breast cancer tumors and cells. Silenced miR-132/-212 expression induced DOX accumulation in MCF-7/ADR cells, while overexpression of miR-132/-212 led to breast cancer resistance protein (BCRP)-based DOX efflux in MCF-7 cells. Further study showed that up-regulation of miR-132/-212 in MCF-7/ADR cells suppressed the expression of PTEN, a target gene of miR-132/-212, which activated AKT phosphorylation and the NF-κB pathway and led to increased BCRP expression. Down-regulation of miR-132/-212 sensitized MCF-7/ADR cells to DOX. Mechanistic investigations suggested that miR-132/-212 enhancement was a result of NF-κB-mediated transactivation of the pri-miR-132/-212 gene. Taken together, our findings are among the first to demonstrate a novel aspect of the miR-132/-212-PTEN-AKT/NF-κB-BCRP pathway in the generation of breast cancer resistance and provides a potential method to reverse drug resistance.

Knockdown of prohibitin expression promotes glucose metabolism in eutopic endometrial stromal cells from women with endometriosis.

In this in-vitro study, the effect of prohibitin (PHB) on glucose metabolism in eutopic endometrial stromal cells from women with endometriosis was investigated. Endometrial stromal cells were isolated from endometrium in women with endometriosis, in women without endometriosis, or from endometrioma tissues. Glucose metabolic phenotype of stromal cells were examined in vitro. Quantitative polymerase chain reaction was used to measure the mRNA expression of glycolysis-related genes. Glucose consumption and lactate production were examined after knockdown of PHB expression in women with endometriosis with siRNA. In endometrioma tissue, significantly increased glucose consumption, lactate production and aberrant expression of glycolysis-related enzymes were found in women with endometriosis compared with women who do not have endometriosis (P < 0.05 versus P < 0.001). In women with endometriosis, PHB mRNA and protein were under-expressed in endometrioma tissue; in women without endometriosis, PHB mRNA and protein were over-expressed. Knockdown of PHB expression in women with endometriosis increased glucose consumption, although it had no effect on lactate production. This study suggests that aberrant expression of glycolysis-related enzymes in endometrioma tissue is associated with enhanced glycolytic metabolism. The malignant-like feature may be partially caused by low-expression of PHB gene in endometriotic stromal cells.

[A two-dimensional reference map of mouse ovary proteins].

OBJECTIVE: To perform a preliminary proteomic analysis of mouse ovaries and to study the protein's function in mouse ovary. METHODS: The two-dimensional gel electrophoresis (2-DE) and matrix assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) were used to analyze mouse ovarian proteome. A 12.5% sodium dodecyl sulfate (SDS) reference gel was generated by immobilized pH gradient isoelectric focusing of mouse ovary proteins in a non-linear gradient (pH 3-10). And GRP78 was selected to perform with immunohistochemistry within mouse ovaries. RESULTS: Based on peptide mass fingerprinting, 52 proteins were identified and classified into seven functional groups: Cell/organism defense and antioxidant, cell signaling/communications proteins, cell structure/motility proteins, metabolism proteins, RNA synthesis processing, protein synthesis and processing, and unclassified proteins. The immunoreactivity of GRP78 was detected in GCs in the follicular, and with during GCs Luteinizing in the menstrual cycle, the protein expression (brown) increased continually and came to a head when ovulation happened. CONCLUSION: This work provides a first step toward the establishment of a systematic ovary protein database and stands as a valuable resource for molecular analyses of normal and pathologic conditions affecting mouse ovaries.