p,p'-DDT induces apoptosis in human endometrial stromal cells via the PI3K/AKT pathway and oxidative stress.

OBJECTIVE: Bis-[4-chlorophenyl]-1,1,1-trichloroethane (DDT), one of the most widely used synthetic pesticides, is an endocrine-disrupting chemical with the potential to interfere with the human reproductive system. The effects of DDT and one of its metabolites, p,p'-DDT, on human endometrial stromal cells (ESCs) and health outcomes remain unknown. In this study, we investigated whether p,p'-DDT induces an imbalance in cell proliferation and apoptosis in human ESCs via oxidative stress. METHODS: We assessed apoptosis in ESCs by quantifying the expression of markers associated with both intrinsic and extrinsic pathways. Additionally, we measured levels of reactive oxygen species (ROS), antioxidant enzyme activity, and estrogen receptors (ERs). We also examined changes in signaling involving nuclear factor kappa-light-chain-enhancer of activated B cells. RESULTS: Following treatment with 1,000 pg/mL of p,p'-DDT, we observed an increase in Bax expression, a decrease in Bcl-2 expression, and increases in the expression of caspases 3, 6, and 8. We also noted a rise in the generation of ROS and a reduction in glutathione peroxidase expression after treatment with p,p'-DDT. Additionally, p,p'-DDT treatment led to changes in ER expression and increases in the protein levels of phosphatidylinositol 3-kinase (PI3K), phospho-protein kinase B (phospho-AKT), and phospho-extracellular signal-regulated kinase (phospho-ERK). CONCLUSION: p,p'-DDT was found to induce apoptosis in human ESCs through oxidative stress and an ER-mediated pathway. The activation of the PI3K/AKT and ERK pathways could represent potential mechanisms by which p,p'-DDT prompts apoptosis in human ESCs and may be linked to endometrial pathologies.

Triphenyl phosphate activates estrogen receptor α/NF-κB/ cyclin D1 signaling to stimulate cell cycle progression in human Ishikawa endometrial cancer cells.

OBJECTIVE: Triphenyl phosphate (TPHP) is one of the most commonly used organophosphorus flame retardants that may accumulate in the environment. However, its effects on human reproductive organs have not been well studied. We aimed to investigate the in vitro effects of TPHP in human Ishikawa endometrial cancer cells to elucidate how TPHP exposure disrupts intracellular signaling and cell proliferation in reproductive tissues. METHODS: Human Ishikawa endometrial cancer cells were exposed to TPHP. RESULTS: Exposure to TPHP elevated the levels of estrogen receptor (ER) α and progesterone receptor-B and reduced ER ß in human Ishikawa endometrial cancer cells. TPHP stimulated phosphoinositide 3-kinase/protein kinase B and mitogenactivated protein kinase/ extracellular signal-regulated kinases 1/2 kinase signaling, which may contribute to the activation of ER function and induce nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in human Ishikawa endometrial cancer cells. Activated ER and NF-κB stimulate the expression of cyclin D1/ cyclin-dependent kinase (CDK) 4/CDK6, indicating cell cycle progression and proliferation. CONCLUSION: This report may provide new information on the molecular mechanisms underlying how TPHP exposure dysregulates the cellular physiology of the human endometrium.

Chemical Probes and Activity-Based Protein Profiling for Cancer Research.

Chemical probes can be used to understand the complex biological nature of diseases. Due to the diversity of cancer types and dynamic regulatory pathways involved in the disease, there is a need to identify signaling pathways and associated proteins or enzymes that are traceable or detectable in tests for cancer diagnosis and treatment. Currently, fluorogenic chemical probes are widely used to detect cancer-associated proteins and their binding partners. These probes are also applicable in photodynamic therapy to determine drug efficacy and monitor regulating factors. In this review, we discuss the synthesis of chemical probes for different cancer types from 2016 to the present time and their application in monitoring the activity of transferases, hydrolases, deacetylases, oxidoreductases, and immune cells. Moreover, we elaborate on their potential roles in photodynamic therapy.

TMI-1, TNF-α-Converting Enzyme Inhibitor, Protects Against Paclitaxel-Induced Neurotoxicity in the DRG Neuronal Cells In Vitro.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) negatively impacts cancer survivors' quality of life and is challenging to treat with existing drugs for neuropathic pain. TNF-α is known to potentiate TRPV1 activity, which contributes to CIPN. Here, we assessed the role of TMI-1, a TNF-α-converting enzyme inhibitor, in paclitaxel (PAC)-induced neurotoxicity in dorsal root ganglion (DRG) cells. Materials and Methods: Immortalized DRG neuronal 50B11 cells were cultured and treated with PAC or PAC with TMI-1 following neuronal differentiation. Cell viability, analysis of neurite growth, immunofluorescence, calcium flow cytometry, western blotting, quantitative RT-PCR, and cytokine quantitation by ELISA were performed to determine the role of TMI-1 in neurotoxicity in neuronal cells. Results: PAC administration decreased the length of neurites and upregulated the expression of TRPV1 in 50B11 cells. TMI-1 administration showed a protective effect by suppressing inflammatory signaling, and secretion of TNF-α. Conclusion: TMI-1 partially protects against paclitaxel-induced neurotoxicity by reversing the upregulation of TRPV1 and decreasing levels of inflammatory cytokines, including TNF-α, IL-1ß, and IL-6 in neuronal cells.

Dabigatran Acylglucuronide, the Major Metabolite of Dabigatran, Shows a Weaker Anticoagulant Effect than Dabigatran.

Dabigatran (DAB) is an orally administered thrombin inhibitor. Both DAB and its main metabolite dabigatran acylglucuronide (DABG) have established anticoagulant effects. Here, we aimed to compare the relative anticoagulant effects of DABG and DAB in humans. Anticoagulant effects of DAB and DABG were measured in vitro using a thrombin generation assay. Additionally, their effects on other coagulation assays including PT, aPTT, TT, and fibrinogen were compared. Both DAB and DABG showed inhibitory effects on thrombin generation in a dose-dependent manner, but DABG exhibited a weaker inhibitory effect than that of DAB. The IC50 values of DAB and DABG on thrombin generation AUC were 134.1 ng/mL and 281.9 ng/mL, respectively. DABG also exhibited weaker anticoagulant effects than DAB on PT, aPTT, and TT. The results of the present study indicate that the anticoagulant effect of DABG, a main active DAB metabolite, is weaker than that of DAB.

RNA-sequencing identification and validation of genes differentially expressed in high-risk adenoma, advanced colorectal cancer, and normal controls.

Distinct gene expression patterns that occur during the adenoma-carcinoma sequence need to be determined to analyze the underlying mechanism in each step of colorectal cancer progression. Elucidation of biomarkers for colorectal polyps that harbor malignancy potential is important for prevention of colorectal cancer. Here, we use RNA sequencing to determine gene expression profile in patients with high-risk adenoma treated with endoscopic submucosal dissection by comparing with gene expression in patients with advanced colorectal cancer and normal controls. We collected 70 samples, which consisted of 27 colorectal polyps, 24 cancer tissues, and 19 normal colorectal mucosa. RNA sequencing was performed on an Illumina platform to select differentially expressed genes (DEGs) between colorectal polyps and cancer, polyps and controls, and cancer and normal controls. The Kyoto Gene and Genome Encyclopedia (KEGG) and gene ontology (GO) analysis, gene-concept network, GSEA, and a decision tree were used to evaluate the DEGs. We selected the most highly expressed genes in high-risk polyps and validated their expression using real-time PCR and immunohistochemistry. Compared to patients with colorectal cancer, 82 upregulated and 24 downregulated genes were detected in high-risk adenoma. In comparison with normal controls, 33 upregulated and 79 downregulated genes were found in high-risk adenoma. In total, six genes were retrieved as the highest and second highest expressed in advanced polyps and cancers among the three groups. Among the six genes, ANAX3 and CD44 expression in real-time PCR for validation was in good accordance with RNA sequencing. We identified differential expression of mRNAs among high-risk adenoma, advanced colorectal cancer, and normal controls, including that of CD44 and ANXA3, suggesting that this cluster of genes as a marker of high-risk colorectal adenoma.

Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation.

BACKGROUND AND AIMS: Colitis-associated cancer (CAC) is one of the most serious complications in patients with inflammatory bowel disease. Sphingosine kinase 1 (Sphk1) is a key enzyme in the sphingolipid pathway and has oncogene potential for inducing both initiation and progression of tumors. The aim of this work is to characterize the role of epithelial Sphk1 in mouse colitis and CAC models. METHODS: We investigated the roles of Sphk1 in CAC by conditional deletion of Sphk1 in intestinal epithelial cells (IECs). RESULTS: CAC was induced in both Sphk1ΔIEC/ApcMin/+ and Sphk1IEC/ApcMin/+ mice by administration of 2% dextran sodium sulfate (DSS) for 7 days. Genetic deletion of Sphk1 significantly reduced the number and size of tumors in ApcMin/+ mice. Histologic grade was more severe in Sphk1ΔIEC/ApcMin/+ mice compared with Sphk1IEC/ApcMin/+ mice (invasive carcinoma, 71% versus 13%, p < 0.05). Deletion of Sphk1 decreased mucosal proliferation and inhibited STAT3 activation and genetic expression of cyclin D1 and cMyc in tumor cells. Conditional deletion of Sphk1 using CRISPR-Cas9 in HCT 116 cells inhibited interleukin (IL)-6-mediated STAT3 activation. CONCLUSIONS: Epithelial conditional deletion of Sphk1 inhibits CAC in ApcMin/+-DSS models in mice by inhibiting STAT3 activation and its target signaling pathways.

Bisphenol A modulates inflammation and proliferation pathway in human endometrial stromal cells by inducing oxidative stress.

Bisphenol A (BPA) has been implicated in altered human reproductive function. The oxidative stress or change of inflammatory signaling may appear a key factor in the biological changes of the human endometrium. Using MTT assay we assessed BPA mediated modulation of oxidative stress and inflammation responses in human endometrial stromal cells (ESCs). According to the results, reactive oxygen species (ROS) generation was highest upon exposure to 1000 pmol BPA. Increased mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) were demonstrated. Gene expression and release of inflammatory cytokines were increased. Upon BPA exposure, elevated estrogen receptor (ER)-α expression levels in ESCs correlated with changes in oxidative stress, inflammatory gene expression and signal changes in cellular proliferation signaling. These findings support that BPA induces oxidative stress and activates inflammatory signals in cultured ESCs via ER-α. Together, this result may provide insight into the association between BPA exposure and endometrium-related disorders.

Assessment of the effects of prostaglandins on myometrial and leiomyoma cells in vitro through microRNA profiling.

It is well known that prostaglandin (PG) E2 and PGF2α are secreted in copious amounts from the menstruating uterus. The aim of the present study was to determine whether PGs affect the growth of uterine leiomyomas (ULs) to the same extent as estrogen or progesterone (P4). The present study evaluated the expression of eight microRNAs (miRNAs) by reverse transcription­quantitative polymerase chain reaction (RT­qPCR) through treatment with estradiol (E2), P4, PGE2, PGF2α and each antagonist or cyclooxygenase­2 (COX­2) inhibitor of cultured leiomyoma and myometrial cells (LC and MC, respectively). The eight miRNAs were divided into two groups according to their primary biological action, namely apoptosis­regulating miRNAs (let­7a, miR­21, miR­26a and miR­200a) and inflammation­regulating miRNAs (miR­29b, miR­93, miR­106b and miR­100b). PGE2 induced significantly higher expression of the 3 anti­apoptotic miRs, let­7a, miR­16a and miR­200a, in LC when compared with the non­treated control or E2. PGE2 significantly promoted a greater expression of let­7a and miR­26a in LC when compared with P4. Overall, PGE2 exerted the highest anti­apoptotic and anti­inflammatory effect in LC, which was comparable with E2. It was not observed among the inflammation­regulating miRNAs in LC. PGF2α did not exert effects as prominent as those of PGE2. In MC, PGs and sex steroids exerted no similar effects on MC compared with LC. The present study demonstrated that PGE2 levels during menstruation may affect the growth of preexisting ULs without affecting the normal myometrium. Therefore, the control of secretion of PGs from the menstruating uterus or the administration of antagonists may be an alternative therapy for inhibiting the growth of ULs.

Encapsulation of Multiple Microalgal Cells via a Combination of Biomimetic Mineralization and LbL Coating.

The encapsulation of living cells is appealing for its various applications to cell-based sensors, bioreactors, biocatalysts, and bioenergy. In this work, we introduce the encapsulation of multiple microalgal cells in hollow polymer shells of rhombohedral shape by the following sequential processes: embedding of microalgae in CaCO3 crystals; layer-by-layer (LbL) coating of polyelectrolytes; and removal of sacrificial crystals. The microcapsule size was controlled by the alteration of CaCO3 crystal size, which is dependent on CaCl2/Na2CO3 concentration. The microalgal cells could be embedded in CaCO3 crystals by a two-step process: heterogeneous nucleation of crystal on the cell surface followed by cell embedment by the subsequent growth of crystal. The surfaces of the microalgal cells were highly favorable for the crystal growth of calcite; thus, micrometer-sized microalgae could be perfectly occluded in the calcite crystal without changing its rhombohedral shape. The surfaces of the microcapsules, moreover, could be decorated with gold nanoparticles, Fe3O4 magnetic nanoparticles, and carbon nanotubes (CNTs), by which we would expect the functionalities of a light-triggered release, magnetic separation, and enhanced mechanical and electrical strength, respectively. This approach, entailing the encapsulation of microalgae in semi-permeable and hollow polymer microcapsules, has the potential for application to microbial-cell immobilization for high-biomass-concentration cultivation as well as various other bioapplications.

CO2 Capturing and Mineralization by (Mg)-Phyllosilicate Coated with Fabrics.

To promote the practicality of magnesium (Mg)-phyllosilicate as a potent carbonation agent, two inexpensive cotton and nylon fabrics are selected and examined to assess their feasibility for use as supporting media of Mg-phyllosilicate. Mg-phyllosilicate is coated onto the fabrics via a sol-gel method, whose mechanism is explained. The characteristics of the Mg-phyllosilicate coated cotton, along with those of the carbonation products, are explored. Mg-phyllosilicate is found to mediate the carbon dioxide (CO2) mineralization process actively, even on cotton of a supporting material. Conclusively, the obtained results clearly support the potential of mineralization as a feasible option for capturing CO2, in particular with the abiotic catalyst of Mg-phyllosilicate coated onto flexible cotton.

The formation of web-like connection among electrospun chitosan/PVA fiber network by the reinforcement of ellipsoidal calcium carbonate.

The electrospun fibers consist of backbone fibers and nano-branch network are synthesized by loading of ellipsoidal calcium carbonate in the mixture of chitosan/poly(vinyl alcohol) (PVA) followed by electrospinning. The synthesized ellipsoidal calcium carbonate is in submicron size (730.7±152.4 nm for long axis and 212.6±51.3 nm for short axis). The electrospun backbone fibers experience an increasing in diameter by loading of calcium carbonate from 71.5±23.4 nm to 281.9±51.2 nm. The diameters of branch fibers in the web-network range from 15 nm to 65 nm with most distributions of fibers are in 30-35 nm. Calcium carbonate acts as reinforcing agent to improve the mechanical properties of fibers. The optimum value of Young's modulus is found at the incorporation of 3 wt.% of calcium carbonate in chitosan/PVA fibers, which is enhanced from 15.7±3 MPa to 432.4±94.3 MPa. On the other hand, the ultimate stress of fibers experiences a decrease. This result shows that the fiber network undergoes changes from flexible to more stiff by the inclusion of calcium carbonate. The thermal analysis results show that the crystallinity of polymer is changed by the existence of calcium carbonate in the fiber network. The immersion of fibers in simulated body fluid (SBF) results in the formation of apatite on the surface of fibers.

Di-(2-ethylhexyl)-phthalate induces oxidative stress in human endometrial stromal cells in vitro.

Di-(2-ethylhexyl)-phthalate (DEHP) accumulates in the environment, and its exposure is possibly associated with endocrine-related disease in women of reproductive age. The effects of DEHP on human endometrial cells are unknown. We treated human endometrial stromal cells with 10, 100, and 1000 pmol of DEHP and measured reactive oxygen species (ROS) generation, expression levels of antioxidant enzymes, alteration of MAPK/NF-κB signaling and hormonal receptors. DEHP increased reactive oxygen species (ROS) generation and decreased expression of superoxide dismutase (SOD), glutathione peroxidase (GPX), heme oxygenase (HO), and catalase (CAT). By DEHP exposure, p-ERK/p-p38 and NF-κB mediated transcription was increased. Additionally, DEHP induced estrogen receptor-α (ER-α) expression in a dose-dependent manner. This study shows the need for future mechanistic studies of oxidative stress, MAPK/NF-κB signaling, and ER-α as molecular mediators of DEHP-associated endometrial stromal cell alterations, which may be associated with the development of endocrine-related disease such as endometriosis.

Preparation of yolk-shell and filled Co9S8 microspheres and comparison of their electrochemical properties.

In this study, we report the first preparation of phase-pure Co9S8 yolk­shell microspheres in a facile two-step process and their improved electrochemical properties. Yolk­shell Co3O4 precursor microspheres are initially obtained by spray pyrolysis and are subsequently transformed into Co9S8 yolk­shell microspheres by simple sulfidation in the presence of thiourea as a sulfur source at 350 °C under a reducing atmosphere. For comparison, filled Co9S8 microspheres were also prepared using the same procedure but in the absence of sucrose during the spray pyrolysis. The prepared yolk­shell Co9S8 microspheres exhibited a Brunauer­Emmett­Teller (BET) specific surface area of 18 m(2) g(−1) with a mean pore size of 16 nm. The yolk­shell Co9S8 microspheres have initial discharge and charge capacities of 1008 and 767 mA h g(−1) at a current density of 1000 mA g(−1), respectively, while the filled Co9S8 microspheres have initial discharge and charge capacities of 838 and 638 mA h g(−1), respectively. After 100 cycles, the discharge capacities of the yolk­shell and filled microspheres are 634 and 434 mA h g(−1), respectively, and the corresponding capacity retentions after the first cycle are 82% and 66%.

One-pot synthesis of manganese oxide-carbon composite microspheres with three dimensional channels for Li-ion batteries.

The fabrication of manganese oxide-carbon composite microspheres with open nanochannels and their electrochemical performance as anode materials for lithium ion batteries are investigated. Amorphous-like Mn3O4 nanoparticles embedded in a carbon matrix with three-dimensional channels are fabricated by one-pot spray pyrolysis. The electrochemical properties of the Mn3O4 nanopowders are also compared with those of the Mn3O4-C composite microspheres possessing macropores resembling ant-cave networks. The discharge capacity of the Mn3O4-C composite microspheres at a current density of 500 mA g(-1) is 622 mA h g(-1) after 700 cycles. However, the discharge capacity of the Mn3O4 nanopowders is as low as 219 mA h g(-1) after 100 cycles. The Mn3O4-C composite microspheres with structural advantages and high electrical conductivity have higher initial discharge and charge capacities and better cycling and rate performances compared to those of the Mn3O4 nanopowders.

Preparation of a reduced graphene oxide wrapped lithium-rich cathode material by self-assembly.

A lithium-rich cathode material wrapped in sheets of reduced graphene oxide (RGO) and functionalized with polydiallyldimethylammonium chloride (PDDA) was prepared by self-assembly induced from the electrostatic interaction between PDDA-RGO and the Li-rich cathode material. At current densities of 1000 and 2000 mA g(-1), the PDDA-RGO sheet wrapped samples demonstrated increased discharge capacities, increasing from 125 to 155 mA h g(-1) and from 82 to 124 mA h g(-1), respectively. The decreased resistance implied by this result was confirmed from electrochemical impedance spectroscopy results, wherein the charge-transfer resistance of the pristine sample decreased after wrapping with the PDDA-RGO sheets. The PDDA-RGO sheets served as a protective layer sand as a conductive material, which resulted in an improvement in the retention capacity from 56 to 81% after 90 cycles.

Long-term sustainable aluminum precursor solution for highly conductive thin films on rigid and flexible substrates.

To fabricate the highly conductive Al film via a solution process, AlH3 etherates have been a unique Al source despite their chemical instability in solvents and thus lack of long-term sustainability. Herein, we suggest an innovative solution process to overcome the aforementioned drawbacks in AlH3 etherates; AlH3 aminates powder, which can be stored in low temperature surroundings and redissolved in solvents whenever it is needed. Since refrigeration of AlH3 aminates, AlH3{N(CH3)3}, was very effective to prevent its chemical degradation, Al film with excellence and uniformity in electrical and mechanical properties was successfully fabricated even by the 180-day stored AlH3{N(CH3)3} dissolved in solvents. Moreover, the applicability of long-term stored AlH3{N(CH3)3} to electronic devices was experimentally demonstrated by the successful operation of LED lamps connected to the Al pattern films on glass, PET, and paper substrates.

Cyclooxygenase-2 inhibitor, celecoxib, inhibits leiomyoma cell proliferation through the nuclear factor κB pathway.

Our aim was to investigate whether celecoxib, a cyclooxygenase 2 (COX-2) inhibitor, decreases the in vitro proliferation of leiomyoma cells if the inflammatory pathway is blocked. Menstruation is an inflammation of uterus that produces cytokines and prostanoids, but the inflammatory mechanism underlying the growth of leiomyoma remains unexplained. Using in vitro cultures of leiomyoma cells obtained from 5 patients who underwent hysterectomy, cell proliferation, inflammatory signaling, transcription factors, growth factors, and extracellular matrix were examined by (4,5-dimethylthiaxol-2-yi)-2,5-diphenyltetraxolium bromide assay, immunoblotting, and quantitative polymerase chain reaction. Prostaglandin E2 was used to induce menstruation-like condition in the cells. We found that celecoxib inhibited COX-2 through the expression of nuclear factor κB in the cells. Celcoxib also decreased the gene expression of interleukin 6, tumor necrosis factor α, collagen A, fibronectin, platelet-derived growth factor, epidermal growth factor, and transforming growth factor ß. In conclusion, the present study indicated that celecoxib could inhibit leiomyoma cell proliferation through blocking the inflammatory pathway that is probably one of the mechanisms underlying its pathogenesis.

Design and fabrication of new nanostructured SnO2-carbon composite microspheres for fast and stable lithium storage performance.

One-pot method for metal oxide-carbon composite microsphere with three-dimensional ordered macroporous (3DOM) structure is first introduced. The 3DOM structured SnO2 -carbon microspheres prepared as the first target material show superior electrochemical properties as anode material for lithium ion batteries. The newly developed process can be applied to the preparation of 3DOM-structured metal oxide-carbon composite microspheres for wide applications.

Excellent electrochemical properties of yolk-shell MoO3 microspheres formed by combustion of molybdenum oxide-carbon composite microspheres.

Yolk-shell MoO3 microspheres are prepared by a two-step process in which molybdenum oxide-carbon (MoO(x)-C) composite microspheres are first obtained by spray pyrolysis, followed by combustion at 400 °C in air. The yolk-shell microspheres exhibit excellent electrochemical properties and structural stability.