FKBP38 suppresses endometrial cancer cell proliferation and metastasis by inhibiting the mTOR pathway.

Endometrial cancer (EC) is a common gynecological malignancy, and advanced-stage or recurrent EC is associated with a high mortality rate owing to the ineffectiveness of currently available treatments. FK506-binding protein 38 (FKBP38) is a member of the immunophilin family and inhibits melanoma and breast cancer cell metastasis. However, the functions of FKBP38 and its potential mechanism in EC remain unclear. Herein, we analyzed the expression levels of FKBP38 in EC cells and found that the FKBP38 expression was high in Ishikawa cells, and low in AN3CA cells, traditionally considered a low grade and a high grade cell line, respectively, in pathology classification. Moreover, FKBP38 inhibited cell proliferation, migration and invasion in EC cells, FKBP38 knockdown significantly promoted tumor growth of Ishikawa cells in a subcutaneous xenograft model and increased the number of lung metastases of Hec-1-A cells in a metastatic mouse model. Furthermore, FKBP38 suppressed several target proteins of epithelial-to-mesenchymal transition (EMT) and reduced the phosphorylation of ribosomal S6 protein (S6), eukaryotic initiation factor 4E-binding protein 1 (4EBP-1), indicating the potent inhibition of the mammalian target of rapamycin (mTOR) pathway. Meanwhile, the inhibition of mTOR neutralized the elevation of EC cell proliferation, migration and invasion after FKBP38 knockdown. In summary, FKBP38 would exert a tumor-suppressing role by modulating the mTOR pathway. Our results indicate that FKBP38 may be considered as a factor of EC metastasis and a new target for EC therapeutic intervention.

Eicosapentaenoic acid metabolites promotes the trans-differentiation of pancreatic α cells to ß cells.

Type 1 diabetes mellitus (T1DM) is characterized by life-threatening absolute insulin deficiency. Although ω-3 polyunsaturated fatty acids (PUFAs) displayed significant anti-hyperglycemic activity, the insulinotropic effects of their metabolites remain unknown. In this study, we took advantage of a transgenic model, mfat-1, that overexpresses an ω-3 desaturase and can convert ω-6 PUFAs to ω-3 PUFAs. Eicosapentaenoic acid (EPA) was sharply elevated in the pancreatic tissues of mfat-1 transgenic mice compared with wild-type (WT) mice. In contrast to the WT mice, the mfat-1 transgenics did not develop overt diabetes and still maintained normal blood glucose levels and insulin secretion following streptozotocin-treatment. Furthermore, under the condition of pancreatic ß-cell damage, co-incubation of the metabolites of EPA produced from the CYP 450 pathway with isolated islets promoted the overexpression of insulin as well as ß-cell specific markers, pdx1 and Nkx6.1 in pancreatic α-cells. Addition of EPA metabolites to the cultured glucagon-positive α-cell lines, a series of pancreatic ß-cell markers were also found significantly elevated. Combined together, these results demonstrated the effects of ω-3 PUFAs and their metabolites on the trans-differentiation from α-cells to ß-cells and its potential usage in the intervention of T1DM.

Adverse childhood experiences in patients with schizophrenia: related factors and clinical implications.

The relationship between adverse childhood experiences (ACEs) and the development of psychotic symptoms is not well understood. Therefore, this study aimed to investigate the frequency and distribution of ACEs among patients with schizophrenia and their potential correlation with symptomatology and personality pathology. We conducted a cross-sectional study involving 571 patients with schizophrenia in Shanghai, China. Symptomatology was assessed using the Positive and Negative Symptoms Scale (PANSS) and personality pathology was assessed using the Personality Diagnostic Questionnaire Fourth Edition Plus (PDQ-4+). ACEs were assessed using the Child Trauma Questionnaire-Short Form (CTQ-SF). ACEs were highly prevalent, with 80.8% of the patients with schizophrenia reporting at least one ACE. The three most common types of ACE were physical neglect (69.8%), emotional neglect (28.2%), and emotional abuse (22.9%). For specific ACE, emotional abuse was significantly associated with PD traits, whereas emotional and physical neglect types of ACE was significantly associated with negative symptoms. A higher level of physical abuse was more commonly reported by men, younger individuals, and those with a higher level of antisocial PD traits. Higher levels of physical neglect were associated with more severe negative symptoms. ACEs are commonly observed in patients with schizophrenia. Therefore, it is strongly recommended that this clinical population be provided with a comprehensive assessment and individualized intervention for those exposed to specific ACEs.

Endogenous production of ω-3 polyunsaturated fatty acids mitigates cisplatin-induced myelosuppression by regulating NRF2-MDM2-p53 signaling pathway.

Cisplatin is a chemotherapy medication used to treat a wide range of cancers. A common side effect of cisplatin is myelosuppression. Research suggests that oxidative damages are strongly and consistently related to myelosuppression during cisplatin treatment. ω-3 polyunsaturated fatty acids (PUFAs) can enhance the antioxidant capacity of cells. Herein, we investigated the protective benefit of endogenous ω-3 PUFAs on cisplatin-induced myelosuppression and the underlying signaling pathways using a transgenic mfat-1 mouse model. The expression of mfat-1 gene can increase endogenous levels of ω-3 PUFAs by enzymatically converting ω-6 PUFAs. Cisplatin treatment reduced peripheral blood cells and bone marrow nucleated cells, induced DNA damage, increased the production of reactive oxygen species, and activated p53-mediated apoptosis in bone marrow (BM) cells of wild-type mice. In the transgenics, the elevated tissue ω-3 PUFAs rendered a robust preventative effect on these cisplatin-induced damages. Importantly, we identified that the activation of NRF2 by ω-3 PUFAs could trigger an antioxidant response and inhibit p53-mediated apoptosis by increasing the expression of MDM2 in BM cells. Thus, endogenous ω-3 PUFAs enrichment can strongly prevent cisplatin-induced myelosuppression by inhibiting oxidative damage and regulating the NRF2-MDM2-p53 signaling pathway. Elevation of tissue ω-3 PUFAs may represent a promising treatment strategy to prevent the side effects of cisplatin.

Removal of malodorant skatole by two enriched microbial consortia: Performance, dynamic, function prediction and bacteria isolation.

Malodor emission has become one of the major challenges in animal husbandry. Skatole, one of the most offensive odorous compounds, can cause several diseases to organisms and is resistant to biodegradation. However, the microbial community information for skatole degradation has yet to be reported. In this study, the aerobic sequencing batch reactors with two different inocula were constructed. Both Group N (sample from cattle house) and Group E (sample from goose house) could efficiently degrade skatole after 70 days operation under conditions of pH 7.0-9.0 and temperature 20-40 °C. High-throughput sequencing results showed that the α-diversity in Group N was higher than that in Group E, while neither of them changed during the whole operation process. Bacterial community structures in both groups shifted. Generally, Lactococcus, Pseudomonas and Flavobacterium remarkably reduced, while Arthrobacter became the dominant population. Function prediction results indicated that the xenobiotics biodegradation and metabolism category was significantly up-regulated in Group E but remained unchanged in Group N. On the other hand, culture-dependent technique was applied and ten bacteria were obtained from the sludges. Two strains belonged to Rhodococcus, a minor genus in the communities, were firstly proven to harbor excellent skatole-degrading capacity. This study proved that skatole could be effectively removed by activated sludges, and the non-core bacteria Rhodococcus would be functionally important in the degradation process. These findings provide new insights into our understanding of skatole biotransformation process, and offer valuable bacterial resources for bioremediation application.

Extraction, identification, and antioxidant property evaluation of limonin from pummelo seeds.

Limonin, the main bioactive phytochemical constituent of limonoids with multi-functions, is enriched in citrus fruits and often found at a high concentration in citrus seeds. The present study was attempted to introduce a new and efficient extraction method to isolate limonoids from pummelo seeds, and to evaluate the antioxidant property of the main constituent limonin in HepG2 cells. Three key single factors were identified for the extraction of limonoids from pummelo seeds using the Box-Behnken experiment design of response surface methodology (RSM), and the optimized extraction parameters were treatment with 89.68 mL of anhydrous acetone for 4.62 h at 78.94 °C, while the yield of limonoids was 11.52 mg/g. The structure of isolated main constituent of the limonoids was further identified as limonin by Fourier transform infrared (FT-IR) spectrometer and nuclear magnetic resonance (NMR) spectrum. Moreover, the molecular data in HepG2 cells revealed that limonin exerted its anti-oxidant property mainly by the activation of nuclear factor (erythroid-2)-like 2 (Nrf2)/kelch-like ECH-associated protein 1 (Keap1)- antioxidant response element (ARE) pathway in the form of transcriptional regulation of Nrf2 mRNA and posttranscriptional regulation of Nrf2/Keap1 system. These results demonstrate that pummelo seeds are an ideal source of limonoids, and limonin is proved to exert its anti-oxidant property by the activation of Nrf2/Keap1 pathway.