Upregulation of autotaxin by oxidative stress via Nrf2 activation: A novel insight into the compensation mechanism in preeclamptic placenta.

The response of autotaxin (ATX)-lysophosphatidic acid (LPA) signaling system to placental oxidative stress (OS) and its significance to preeclampsia were investigated. For this purpose, oxidative stress index (OSI) and ATX levels were measured in the serum of pregnant women with preeclampsia. The expression levels of ATX and LPA receptors were assessed in trophoblast cells under high OS and glucose deprivation/re-oxygenation (OGD/R) conditions, with particular emphasis on the antioxidative nuclear factor erythroid 2-related factor 2 (NRF2) pathway. The influence of ATX-LPA signaling on cell migration was also evaluated using the wound healing assay. ATX concentrations and OSI in the serum were found to be elevated in preeclamptic women. The serum ATX levels were also positively correlated with OSI. Trophoblast cells responded to OS by increasing ATX mRNA expression concomitantly with intranuclear translocation of Nrf2, whereas inhibition of Nrf2 activation reverted this effect. The ATX-LPA signaling pathway facilitated trophoblast cell motility after Nrf2 activation. In conclusion, OS accumulation in preeclamptic placenta may activate the ATX-LPA system in trophoblasts via the Nrf2 pathway to sustain trophoblast functionality.

Hypoxia-inducible factor-1ß is essential for upregulation of the hypoxia-induced FLT1 gene in placental trophoblasts.

Placental hypoxia and increased levels of maternal blood anti-angiogenic protein, soluble fms-like tyrosine kinase-1 (sFLT1), are associated with the pathogenesis of pre-eclampsia. We have demonstrated that hypoxia-inducible factor (HIF)-2α mediates the upregulation of the hypoxia-induced FLT1 gene in trophoblasts and their cell lines. Here, we investigated the involvement of HIF-1ß, which acts as a dimerization partner for HIF-α, in the upregulation of the FLT1 gene via hypoxia. We confirmed the interactions between HIF-1ß and HIF-2α in the nuclei of BeWo, JAR and JEG-3 cells under hypoxia via co-immunoprecipitation. We found that hypoxia-induced upregulation of the FLT1 gene in BeWo cells and secretion of sFLT1 in human primary trophoblasts were significantly reduced by siRNAs targeting HIF-1ß. Moreover, the upregulation of the FLT1 gene in BeWo cells induced by dimethyloxaloylglycine (DMOG) was also inhibited by silencing either HIF-2α or HIF-1ß mRNA. It was recently shown that DNA demethylation increases both basal and hypoxia-induced expression levels of the FLT1 gene in three trophoblast-derived cell lines. In the demethylated BeWo cells, siRNAs targeting HIF-2α and HIF-1ß suppressed the further increase in the expression levels of the FLT1 gene due to hypoxia or treatment with DMOG. However, luciferase reporter assays and bisulfite sequencing revealed that a hypoxia response element (-966 to -962) of the FLT1 gene is not involved in hypoxia or DMOG-induced upregulation of the FLT1 gene. These findings suggest that HIF-1ß is essential for the elevated production of sFLT1 in the hypoxic trophoblasts and that the HIF-2α/HIF-1ß complex may be a crucial therapeutic target for pre-eclampsia.

Risk factors and a prediction model for lower limb lymphedema following lymphadenectomy in gynecologic cancer: a hospital-based retrospective cohort study.

BACKGROUND: Lower limb lymphedema (LLL) is a chronic and incapacitating condition afflicting patients who undergo lymphadenectomy for gynecologic cancer. This study aimed to identify risk factors for LLL and to develop a prediction model for its occurrence. METHODS: Pelvic lymphadenectomy (PLA) with or without para-aortic lymphadenectomy (PALA) was performed on 366 patients with gynecologic malignancies at Yaizu City Hospital between April 2002 and July 2014; we retrospectively analyzed 264 eligible patients. The intervals between surgery and diagnosis of LLL were calculated; the prevalence and risk factors were evaluated using the Kaplan-Meier and Cox proportional hazards methods. We developed a prediction model with which patients were scored and classified as low-risk or high-risk. RESULTS: The cumulative incidence of LLL was 23.1% at 1 year, 32.8% at 3 years, and 47.7% at 10 years post-surgery. LLL developed after a median 13.5 months. Using regression analysis, body mass index (BMI) ≥25 kg/m2 (hazard ratio [HR], 1.616; 95% confidence interval [CI], 1.030-2.535), PLA + PALA (HR, 2.323; 95% CI, 1.126-4.794), postoperative radiation therapy (HR, 2.469; 95% CI, 1.148-5.310), and lymphocyst formation (HR, 1.718; 95% CI, 1.120-2.635) were found to be independently associated with LLL; age, type of cancer, number of lymph nodes, retroperitoneal suture, chemotherapy, lymph node metastasis, herbal medicine, self-management education, or infection were not associated with LLL. The predictive score was based on the 4 associated variables; patients were classified as high-risk (scores 3-6) and low-risk (scores 0-2). LLL incidence was significantly greater in the high-risk group than in the low-risk group (HR, 2.19; 95% CI, 1.440-3.324). The cumulative incidence at 5 years was 52.1% [95% CI, 42.9-62.1%] for the high-risk group and 28.9% [95% CI, 21.1-38.7%] for the low-risk group. The area under the receiver operator characteristics curve for the prediction model was 0.631 at 1 year, 0.632 at 3 years, 0.640 at 5 years, and 0.637 at 10 years. CONCLUSION: BMI ≥25 kg/m2, PLA + PALA, lymphocyst formation, and postoperative radiation therapy are significant predictive factors for LLL. Our prediction model may be useful for identifying patients at risk of LLL following lymphadenectomy. Providing an intensive therapeutic strategy for high-risk patients may help reduce the incidence of LLL and conserve the quality of life.