Effects of inhibiting the PI3K/Akt/mTOR signaling pathway on the pain of sciatic endometriosis in a rat model.

This study investigated the relationship between the pain of sciatic endometriosis and the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. Adult female Sprague-Dawley rats successfully received sciatic endometriosis induction. Mechanical paw withdrawal threshold and paw withdrawal latency were recorded to assess the mechanical hypersensitivity and thermal hyperalgesia. Quantitative real-time PCR, Western blotting, and enzyme-linked immunosorbent assays were used to detect PI3K, Akt, and mTOR expressions and their phosphorylation as well as the expressions of substance P, calcitonin gene-related peptide (CGRP), and nerve growth factor (NGF). Mechanical paw withdrawal threshold and paw withdrawal latency significantly decreased after sciatic endometriosis induction in rats; this decrease was ameliorated by inhibiting the PI3K/Akt/mTOR signaling pathway using LY294002. Compared with controls, rats with sciatic endometriosis showed increased PI3K, Akt, and mTOR expressions and elevated p-PI3K, p-Akt, and p-mTOR protein expressions. Higher NGF, substance P, and CGRP expressions were also found in the superficial dorsal horn of the spinal cord in rats with sciatic endometriosis than in control rats 21 days after surgery. Following the injection of LY294002 into rats with sciatic endometriosis, there was a significant decrease in the expressions of NGF, substance P, and CGRP. In conclusion, the inhibition of the PI3K/Akt/mTOR signaling pathway may alleviate endometriosis-associated sciatic nerve pain in a rat model of sciatic endometriosis.

Regulatory B cells contribute to the impaired antitumor immunity in ovarian cancer patients.

Multiple factors in the tumor microenvironment were found to inhibit antitumor adaptive immune responses, allowing tumor persistence and growth. In this study, ascites from ovarian cancer patients were collected. We observed that a population of interleukin-10(+) B (IL-10(+) B) cells was preferentially enriched in the ascites. This population was associated with naive B cell phenotype or IgM or class-switched memory B cell phenotypes. The frequencies of IL-10(+) B cells were negatively correlated with the frequencies of interferon gamma-producing (IFN-g(+)) CD8(+) T cells and were positively correlated with the frequencies of Foxp3(+) CD4(+) T cells. To examine whether increased IL-10(+) B cells in ascites could directly result in increased suppression of IFN-g production by CD8(+) T cells, we cocultured CD8(+) T cells with autologous blood B cells or ascitic B cells and found that CD8(+) T cells cocultured with ascitic B cells demonstrated significantly suppressed IFN-g production. This suppression was in part mediated by IL-10 as well as low CD80/CD86 expression, since depletion of IL-10 and stimulation of CD28 partially reverted IL-10(+) B cell-mediated suppression. Together, these data demonstrated an additional regulatory mechanism in the tumor microenvironment, which utilizes IL-10(+) B cells.

Metal-organic frameworks derived magnetic porous carbon for magnetic solid phase extraction of benzoylurea insecticides from tea sample by Box-Behnken statistical design.

Ferric oxide/carbon (Fe2O3@C) was fabricated via direct carbonization of metal-organic framework of iron (MOF-235) under argon atmosphere. The magnetic Fe2O3 nanoparticles are evenly embedded in porous carbon matrix, while original morphology of MOF-235 was well-maintained. The synthesized Fe2O3@C was used as magnetic sorbent for extracting five benzoylurea insecticides (BUs). The materials exhibited excellent extraction performance, which benefited not only from the strong π-π interaction and hydrophobic interaction (π-conjugated system), but also to the abundant adsorption sites and flexible transport channel (the interconnected 3D porous structure). A three-factor-three-level Box-Behnken design (BBD) was selected to optimize three greatly influential parameters: amount of adsorbent (A), desorption time (B) and volume of desorption solvent (C) by response surface methodology. The established method coupled to HPLC-UV detection showed wide linearity with the range of 0.2-450 µg•L-1, relatively low limits of detection (0.05-0.10 µg•L-1) with the relative standard deviation (RSD) (n = 7) lower t than 5.47%. Moreover, the proposed method was successfully applied to analyze BUs in tea samples and investigate the removal effect of different washing on BUs residues from tea leaf. These results indicated that the synthesized Fe2O3@C is a promising adsorbent material for magnetic solid phase extraction of BUs at trace concentrations from tea samples.

Anti-nociceptive and anti-inflammatory effects of sulforaphane on sciatic endometriosis in a rat model.

Endometriosis of sciatic nerve is a common gynecological disease. Here we aimed to study the anti-inflammatory and anti-nociceptive role of sulforaphane on sciatic nerve endometriosis. The sciatic nerve endometriosis rat model was constructed by autologous implantation of uterine tissue. Sulforaphane was administered intraperitoneally at the dose of 5, 15, 30 and 60 mg/kg/day for 28 days. Behavioral testing was performed at day 7, 14, 21 and 28. At day 28, rats were sacrificed, followed by collecting superficial dorsal horn tissues and lesions. Quantitative real-time PCR and Western blot were performed to assess COX2, Keap1, Nrf2 expression in collected tissues. Enzyme-linked immunosorbent assay was conducted to assess the expression of pro-inflammatory cytokines. Sulforaphane alleviated pain of sciatic endometriosis as evidenced by the increase in paw withdrawal threshold and paw withdrawal latency. Sulforaphane also inhibited ectopic endometrial tissue growth in sciatic endometriosis rat, shown as the shrinkage of lesion size and decreased VEGF levels. IL6, IL-1ß and TNF-α levels were decreased by sulforaphane. Sulforaphane induced DOX2 and INOS suppression and Keap1 and Nrf2 upregulation. Sulforaphane alleviates pain induced by sciatic endometriosis, which is mediated by inhibiting inflammation.

Depletion of tumor-associated macrophages enhances the anti-tumor effect of docetaxel in a murine epithelial ovarian cancer.

Docetaxel (DTXL), a new member of the taxoid family, has been used for cancer treatment. However, increasing cases of DTXL resistance have been reported. Tumor-associated macrophages (TAMs) have been implicated in tumor invasion and chemo-resistance. Eliminating TAMs by inhibiting colony stimulating factor-1 receptor (CSF-1R) has emerged as a promising strategy for cancer treatment. BLZ945 is a CSF-1R inhibitor and has anti-tumor function. In present study, anti-tumor effects of combination treatment of BLZ945 and DTXL were investigated. We established a mouse ovarian cancer model and investigated the effect of BLZ945, DTXL single treatment or combination treatment on TAMs infiltration, tumor growth, CD8+ T cell infiltration and cancer metastasis. DTXL treatment increased the infiltration while BLZ945 induced cell apoptosis in macrophages. DTXL/BLZ945 combination treatment significantly inhibited tumor growth, reduced the abundance of TAMs, increased CD8+ T cell infiltration and prevented lung metastasis. Depletion of Tumor-Associated Macrophages (TAMs) by BLZ945 enhanced the anti-tumor effect of DTXL in a murine epithelial ovarian cancer.

Crocin improves endometriosis by inhibiting cell proliferation and the release of inflammatory factors.

Endometriosis is one of the most common diseases in women. Inflammation and angiogenesis have been shown to be important in pathogenesis of endometriosis. Crocin is known as an anti-inflammatory, anti- proliferation substance. This study was designed to assess the potential effects of crocin on endometriosis. We established the mice model of endometriosis and administrated crocin to the mice. We monitored the endometriotic lesion growth, PCNA and VEGF expression in the lesion. We tested the serum levels of inflammatory cytokines in crocin-treated endometriosis mice. Finally we tested the effect of crocin on endothelial cell apoptosis and proliferation, and cytokine production in LPS-stimulated human monocyte. Crocin inhibited lesion growth in endometriosis mice and prevented PCNA and VEGF expression in the lesions. Crocin decreased the levels of inflammatory cytokines including INF-γ, TNF-α, VEGF and IL-6 in serum. Crocin inhibited endothelial cells proliferation but did not cause apoptosis in endothelia cells. Crocin inhibited cytokine production in LPS-stimulated THP-1 cells in vitro. Crocin protected endometriosis by inhibiting endothelial cells proliferation and preventing inflammatory cytokines production.

Pteisolic acid G, a novel ent-kaurane diterpenoid, inhibits viability and induces apoptosis in human colorectal carcinoma cells.

Human colorectal cancer (CRC) is a major cause of cancer morbidity and mortality, and its incidence rates are increasing in economical transitioning areas globally. To develop efficient chemotherapy drugs for CRC, the present study isolated and identified a novel ent-kaurane diterpenoid from Pteris semipinnata, termed pterisolic acid G (PAG). This ent-kaurane diterpenoid was demonstrated to significantly inhibit the growth of human CRC HCT116 cells in a time- and dose-dependent manner, determined using the Cell Counting Kit-8 assay. Additionally, western blot analysis, Hoechst 33342 staining and cytometry analysis revealed that PAG not only inhibited the viability of HCT116 cells by suppressing the dishevelled segment polarity protein 2/glycogen synthase kinase 3 ß/ß-catenin pathway, but also induced the apoptosis of HCT116 cells by downregulating nuclear factor-κB p65 activity, stimulating p53 expression and promoting the generation of intracellular reactive oxygen species. These results suggest that PAG, a novel inhibitor of the Wnt/ß-catenin pathway and inducer of apoptosis, should be investigated in more detail using in vivo experiments and comprehensive mechanistic studies in order to examine the potential use of PAG as a novel therapeutic agent for the treatment of CRC.

Improving Estimation of Distribution Algorithm on Multimodal Problems by Detecting Promising Areas.

In this paper, a novel multiple sub-models maintenance technique, named maintaining and processing sub-models (MAPS), is proposed. MAPS aims to enhance the ability of estimation of distribution algorithms (EDAs) on multimodal problems. The advantages of MAPS over the existing multiple sub-models based EDAs stem from the explicit detection of the promising areas, which can save many function evaluations for exploration and thus accelerate the optimization speed. MAPS can be combined with any EDA that adopts a single Gaussian model. The performance of MAPS has been assessed through empirical studies where MAPS is integrated with three different types of EDAs. The experimental results show that MAPS can lead to much faster convergence speed and obtain more stable solutions than the compared algorithms on 12 benchmark problems.

Functional polymorphisms in monocyte chemoattractant protein-1 are associated with increased susceptibility to ovarian cancer.

Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. Monocyte chemoattractant protein-1 (MCP-1) is highly expressed in various malignancies and promotes carcinogenesis. The aim of the study was to investigate the association between MCP-1 genetic polymorphisms and the susceptibility to ovarian cancer. MCP-1 rs1024611A/G and rs3760396C/G polymorphisms were examined in 257 ovarian cancer patients and 273 healthy controls. We found that distributions of rs1024611GG genotype and rs3760396GG genotype were clearly increased in ovarian cancer cases compared to healthy donors (odds ratio [OR]=1.93, 95% confidence interval [CI]: 1.13-3.29, p=0.015; OR=3.89, 95% CI: 1.63-9.33, p=0.001). Stratification analyses revealed that patients with serous papillary type had further increased percentage of rs3760396GG genotype than those with other types (OR=3.89, 95% CI: 1.11-13.66, p=0.024). In addition, we evaluated the possible effect of MCP-1 polymorphisms on gene expression by examining the serum level of MCP-1 in patients and controls. Data revealed that subjects carrying rs1024611AG and GG genotypes had a significantly higher serum level of MCP-1 than those with AA genotype. These data suggest that MCP-1 rs1024611A/G and rs3760396C/G polymorphisms are associated with increased susceptibility to ovarian cancer, in which rs1024611A/G may increase serum level of MCP-1 in the Chinese population.