Abortifacient metapristone (RU486 derivative) interrupts CXCL12/CXCR4 axis for ovarian metastatic chemoprevention.

Recent global epidemiological studies revealed the lower ovarian cancer death from long-term use of oral contraceptives. However, the underlying mechanism of action is not clear. Here, we use the abortifacient metapristone (RU486 derivative) to test the hypothesis that the contraceptives might interrupt CXCL12/CXCR4 chemokine axis to inhibit ovarian cancer metastasis. Metapristone at concentrations (

Exploring cancer metastasis prevention strategy: interrupting adhesion of cancer cells to vascular endothelia of potential metastatic tissues by antibody-coated nanomaterial.

BACKGROUND: Cancer metastasis caused by circulating tumor cells (CTCs) accounts for 90% cancer-related death worldwide. Blocking the circulation of CTCs in bloodstream and their hetero-adhesion to vascular endothelia of the distant metastatic organs may prevent cancer metastasis. Nanomaterial-based intervention with adhesion between CTCs and endothelia has not been reported. Driven by the novel idea that multivalent conjugation of EpCAM and Slex antibodies to dendrimer surface may enhance the capacity and specificity of the nanomaterial conjugates for capturing and down-regulating colorectal CTCs, we conjugated the dendrimer nanomaterial with the EpCAM and Slex antibodies, and examined the capacity of the dual antibody-coated nanomaterial for their roles in interrupting CTCs-related cancer metastasis. RESULTS: The antibody-coated nanomaterial was synthesized and characterized. The conjugates specifically bound and captured colon cancer cells SW620. The conjugate inhibited the cells' viability and their adhesion to fibronectin (Fn)-coated substrate or human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. In comparison with SW480 and LoVo cell lines, the activity and adhesion of SW620 to Fn-coated substrate and HUVECs were more specifically inhibited by the dual antibody conjugate because of the higher levels of EpCAM and Slex on SW620 cell surface. The hetero-adhesion between SW620 and Fn-coated substrate, or HUVECs was inhibited by about 60-70%. The dual conjugate showed the inhibition capacity more significant than its corresponding single antibody conjugates. CONCLUSIONS: The present study provides the new evidence that coating nanomaterials with more than one antibody against CTCs may effectively interfere with the interaction between SW620 and HUVECs.

Tin Hybrid Flow Batteries with Ultrahigh Areal Capacities Enabled by Double Gradients.

Tin-based hybrid flow batteries have demonstrated dendrite-free morphology and superior performance in terms of cycle life and energy density. However, the quick accumulation of electrodeposits near the electrode/membrane interface blocks the ion transport pathway during the charging of the battery, resulting to a very limited areal capacity (especially at high current density) that significantly hinders its deployment in long-duration storage applications. Herein, a conductivity-activity dual-gradient design is disclosed by electrically passivating the carbon felt near the membrane/electrode interface and chemically activating the carbon felt near the electrode/current collector interface. In consequence, the tin metals are preferentially plated at the region near electrode/current collector, preventing the ion transport pathway from being easily blocked. The resultant gradient electrode demonstrated an unprecedentedly high areal capacity of 268 mAh cm-2 at a current density of as high as 80 mA cm-2 . Numerical modeling and experimental characterizations show that the dual-gradient electrode differs from conventional electrodes with regard to their reaction current density distribution and electrodeposit distribution during charging. This work demonstrates a new design strategy of 3D electrodes for hybrid flow batteries to induce a desirable distribution of electrodeposits and achieve a high areal capacity at commercially relevant current densities.

High-capacity polysulfide-polyiodide nonaqueous redox flow batteries with a ceramic membrane.

Nonaqueous redox flow batteries (NRFBs) have been regarded as promising large-scale electrochemical energy storage technology due to the wider solvent stable potential windows and greater selection of materials. However, the application of NRFBs is greatly limited considering the low capacity and high cost of active materials. In this work, we design and demonstrate a high-capacity polysulfide (PS)-polyiodide (PI) NRFB in Li-ion based 1,3-dioxolane (DOL) and 1,2-dimethoxyethane (DME) (v/v ∼ 1 : 1) organic electrolyte. The high solubility and low cost of PS (5 M) and PI (4 M) can achieve the high capacity and high applicability of NRFBs, which is attractive for realizing large-scale stationary energy storage. The highest volumetric capacity of 28 Ah L-1 based on a full cell is achieved with 1.5 M PS-4 M PI. The high coulombic efficiency (∼100%) and capacity retention (>99%) for 100 cycles in the PS-PI system is demonstrated by using a Li-ion conducting ceramic membrane. Voltage control is applied for both PS and PI to avoid the formation of irreversible solid Li2S and I2, which ensures the high stability of battery reaction. In situ UV-vis spectroscopy reveals the high reversibility of PS and PI in DOL/DME. A continuous flow mode test of the PS-PI system is also demonstrated to realize >300 hours stable cycling performance which implies good applicability for a long-term process. The successful demonstration of this high-capacity PS-PI nonaqueous system provides a new direction to promote the application of NRFBs in more fields.

High-Capacity CuSi2P3-Based Semisolid Anolyte for Redox Flow Batteries.

Redox flow batteries (RFBs) have attracted more attention due to their ability of decoupling energy and power, but their low energy density has greatly restricted their applications. Semisolid flow batteries (SSFBs) are a kind of RFBs, but they have high energy density. However, there is a lack of research on semisolid anolytes, and thus the application of SSFBs is still in its infancy. In this work, a low-potential (0.6 V vs Li/Li+) CuSi2P3@C-LiPAA composite is synthesized through a simple high-energy mechanical ball milling and impregnation method based on the CuSi2P3 (CSP) compound; then, it is used to prepare a semisolid anolyte, which is able to achieve a high volumetric capacity of 400 Ah L-1 in static mode and 320 Ah L-1 in intermittent-flow mode. This is the highest volumetric capacity of anolyte so far. The effect of adding binder to a composite is also discussed for the first time, which makes the connection between the composite particles closer and the semisolid suspension more uniform so as to obtain stable electrochemical performance. At the same time, through pairing respectively with two types of catholytes, liquid 10-methylphenothiazine (MPT) and semisolid LiFePO4 (LFP), a single-cell voltage of 3 V and more than 100 stable cycles with the Coulombic efficiency of 99% have been achieved by CSP-MPT and CSP-LFP full-cell systems. The result fully demonstrates the applicability of the prepared CSP semisolid anolyte. The synthesis method of adding a binder to the composite in this work also provides a direction for optimizing the suspension for other active materials to be applied to SSFBs in the future.

A low-cost and high-loading viologen-based organic electrode for rechargeable lithium batteries.

Organic active materials are regarded as a very promising choice for lithium batteries because of several outstanding advantages such as low-cost, flexible tunability and pollution-free sources. Viologen compounds are attractive two-electron storage materials with low redox potentials, which are mainly used as anolytes in redox flow batteries (RFBs) considering their high solubility in electrolytes. However, due to their relatively large molecular weight and low density, it is difficult to prepare high-loading and stable-cycling electrodes for lithium battery application. In this research, by adopting 4,4'-bipyridine as the raw material and combining salification with a high-energy ball milling method, a low-solubility and high-stability viologen carbon-coated composite, ethyl viologen dihexafluorophosphate-Ketjen black (EV-KB), is synthesized. Then, by optimizing the electrode preparation process, a high-loading viologen-based electrode is successfully prepared. Salification effectively reduces the solubility of viologen compounds in the electrolyte so that the EV-KB composite can be used in lithium batteries. At the same time, it is pointed out that current collectors and slurry solvents play an important role in achieving the high-loading electrode. By deliberately selecting carbon paper as the current collector and ethanol as the solvent, the EV-KB composite organic electrode with a loading up to 1.5-9 mg cm-2 can achieve a specific capacity of 106-79 mA h g-1 for 400 stable cycles with a coulombic efficiency of 96% as well as a good rate capability. The synthesis method and electrode preparation optimization process introduced in this paper provide a reference for other types of organic active materials to be used in high-loading lithium batteries.

Organic Multiple Redox Semi-Solid-Liquid Suspension for Li-Based Hybrid Flow Battery.

Li-based hybrid flow batteries are very promising in the energy storage market for their high cell voltage and scale-up flexibility. However, the low volumetric capacity of catholyte has limited their practical application. A novel concept of organic multiple redox semi-solid-liquid (MRSSL) suspension was proposed and demonstrated by taking advantage of active materials in both liquid and solid phases in the suspension. In this study, high solubility of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) in the liquid phase and high reversibility of 10-methylphenothiazine (MPT) composite in the solid phase were employed to develop a high-performance and low-cost organic MRSSL Li-based hybrid flow battery. It achieved a small voltage gap (<0.1 V) between liquid and solid phase, high cell voltage (≈3.4 V) and high energy density (260 Wh L-1 ). Due to the synergistic interactions between the liquid-phase TEMPO and the solid-phase MPT, the viscosity of the MRSSL suspension was significantly reduced. An intermittent-flow-mode test of TEMPO-MPT MRSSL suspension was conducted, which proved that the suspension had an applicable cycling performance with high volumetric capacity (50 Ah L-1 ). The organic MRSSL suspension concept offers a new approach to increase the volumetric capacity and energy density of Li-based hybrid flow batteries by combining various low-cost solid and liquid organic active materials.

Mifepristone inhibits ovarian cancer metastasis by intervening in SDF-1/CXCR4 chemokine axis.

SDF-1/CXCR4 signaling axis determines the proliferative potential and site-specific cancer metastasis. Recent studies suggest involvement of the axis and steroidal hormone in ovarian cancer metastasis. Here we hypothesize that mifepristone (RU486), a well-known progesterone-based abortifacient, might interfere this axis and inhibit ovarian cancer metastasis. Mifepristone at concentrations < IC50 inhibited expression of CXCR4 on cell surface of ovarian cancer SKOV-3 and IGROV-1, and reduced expression of the intracellular CXCR4 protein and its related mRNA activated by SDF-1. SDF-1 significantly stimulated proliferation of SKOV-3 and IGROV-1 cells with concomitant increases in intracellular phosphorylation of Akt and ERK. SDF-1 activated cell chemotatic migration and actin polymerization, and up-regulated expression of MMP-2, MMP-9, COX-2, VEGF without influencing the adhesion molecules ICAM-1 and integrins ß1, α1, α3, α5, and α6. The above-mentioned effects of SDF-1 could be antagonized by mifepristone concentration-dependently, and CXCR4 antagonist AMD3100. Mifepristone suppressed the SDF-1-induced migration, invasion and adhesion of the cancer cells to extracellular matrixes. Three-day pretreatment of nude mice with mifepristone (5 and 20 mg/kg/day) followed by a single intraperitoneal IGROV-1 inoculation, along with repeated SDF-1 and mifepristone administrations in turn every other day for 36 days significantly reduced ascitic fluid, metastatic foci, tumor weight and immunoreactivity of CXCR4 in comparison with the SDF-1-treated control. Our results suggest that mifepristone inhibit SDF-1/CXCR4 signaling axis, may have preventive and therapeutic effects on ovarian cancer metastasis.

The traditional Chinese medicine Achyranthes bidentata and our de novo conception of its metastatic chemoprevention: from phytochemistry to pharmacology.

Our recent biosystems analysis revealed similarities between embryonic implantation and cancer cell adhesion, which suggests that abortifacients may be good for safe and effective metastatic chemoprevention targeting circulating tumor cells (CTC). Here we test the hypothesis by using the well-known abortion herb Achyranthes bidentata Blume (A. bidentata). Five compounds were separated from the herb root. Among them, ginsenoside Ro was the most potent in inhibiting embryonic implantation within non-cytotoxic concentrations. It specifically inhibited the metastatic dissemination capability of colon cancer cells HT29, including the migration and invasion ability, and their adhesion to human endothelium through inhibiting integrin αvß6, MMP-2, MMP-9, and ERK phosphorylation by HT29. Pretreatment of nude mice with oral ginsenoside Ro followed by HT29 intravenous inoculation and 40-day oral ginsenoside Ro significantly prevented lung metastasis with downregulation of integrin αvß6 and no toxicity. The present study firstly introduces the new conception of utilizing safe and effective abortion botanic medicines for CTC-based metastatic chemoprevention.

Metapristone suppresses non-small cell lung cancer proliferation and metastasis via modulating RAS/RAF/MEK/MAPK signaling pathway.

BACKGROUND: Metastasis is the key phase of cancer progression that characterizes a more advanced stage and a poorer prognosis. The majority of cancer fatalities occur as a consequence of metastasis. OBJECTIVE: Mifepristone (RU486), a chemical abortifacient, has recently been used in clinical trials for psychotic depression and cancer chemotherapy. As the most predominant biological active metabolite of mifepristone, metapristone is being developed as a novel cancer metastasis chemopreventive agent by us. However, there is no information available to address the effects of metapristone on non-small cell lung cancer (NSCLC). The aim of our study was to investigate the inhibitory effect of metapristone on the proliferation and metastasis of NSCLC cells. METHOD: In the present study, we evaluated the efficacy of metapristone on the growth, migration and invasion in different kinds of NSCLC cells (A549, H1975 and H1299), and further investigated the underlying mechanism of metapristone by real time PCR and western blot assay. RESULTS: Metapristone could significantly inhibit the proliferation, migration and invasion of NSCLC cells through suppressing RAS/RAF/MEK/MAPK and PI3K/AKT signaling pathways. Moreover, metapristone could effectively inhibit the formation of NSCLC cells' cytoskeleton in a concentration-dependent manner, which possibly led to the inhibition of NSCLC cells' migration. CONCLUSION: Overall, it was preliminarily demonstrated that metapristone could be developed as a useful agent to show anti-metastasis activity for NSCLC.

Metapristone (RU486 metabolite) suppresses NSCLC by targeting EGFR-mediated PI3K/AKT pathway.

Therapies targeting epidermal growth factor receptor (EGFR) can effectively treat with non-small cell lung cancer (NSCLC), but NSCLC's drug resistance makes it intractable. Herein, we showed that RU486 metabolite metapristone inhibited the proliferation of various NSCLC cell lines with either wild (A549, H1299, H520) or mutated EGFR (H1975, HCC827). The suppression was resulted from inhibition by metapristone of EGFR signaling pathways through down-regulating the EGFR, PTEN, as well as AKT and ERK proteins. In addition, metapristone inhibited anti-apoptotic marker Bcl-2, and activated pro-apoptotic key signaling proteins caspase-3, and poly (ADP-ribose) polymerase. Metapristone induced A549 and H1975 cell cycle via arrest at the G0-G1 stage. What's more, metapristone inhibited the growth of NSCLC xenografts in BALB/c nude mice through decreasing the expression of tumor growth biomarkers PCNA and EGFR. Taken together, the present study demonstrated that metapristone suppressed NSCLC proliferation by promoting apoptosis via decrease the cellular EGFR-mediated PI3K/AKT pathways. The results suggest metapristone a new treatment for EGFR-overexpressed NSCLC.

A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment.

Metastasis currently remains the predominant cause of breast carcinoma treatment failure. The effective targeting of metastasis-related-pathways in cancer holds promise for a new generation of therapeutics. In this study, we developed an novel Asp-UA conjugate, which was composed of classical "old drug" aspirin and low toxicity natural product ursolic acid for targeting breast cancer metastasis. Our results showed that Asp-UA could attenuate the adhesion, migration and invasion of breast cancer MCF-7 and MDA-MB-231 cells in a more safe and effective manner in vitro. Molecular and cellular study demonstrated that Asp-UA significantly down-regulated the expression of cell adhesion and invasion molecules including integrin α6ß1, CD44 ,MMP-2, MMP-9, COX-2, EGFR and ERK proteins, and up-regulated the epithelial markers "E-cadherin" and "ß-catenin", and PTEN proteins. Furthermore, Asp-UA (80 mg/kg) reduced lung metastasis in a 4T1 murine breast cancer metastasis model more efficiently, which was associated with a decrease in the expression of CD44. More importantly, we did not detect side effects with Asp-UA in mice such as weight loss and main viscera tissues toxicity. Overall, our research suggested that co-drug Asp-UA possessed potential metastasis chemoprevention abilities via influencing EMT and EGFR-mediated pathways and could be a more promising drug candidate for the prevention and/or treatment of breast cancer metastasis.

Sulphur-impregnated flow cathode to enable high-energy-density lithium flow batteries.

Redox flow batteries are promising technologies for large-scale electricity storage, but have been suffering from low energy density and low volumetric capacity. Here we report a flow cathode that exploits highly concentrated sulphur-impregnated carbon composite, to achieve a catholyte volumetric capacity 294 Ah l(-1) with long cycle life (>100 cycles), high columbic efficiency (>90%, 100 cycles) and high energy efficiency (>80%, 100 cycles). The demonstrated catholyte volumetric capacity is five times higher than the all-vanadium flow batteries (60 Ah l(-1)) and 3-6 times higher than the demonstrated lithium-polysulphide approaches (50-117 Ah l(-1)). Pseudo-in situ impedance and microscopy characterizations reveal superior electrochemical and morphological reversibility of the sulphur redox reactions. Our approach of exploiting sulphur-impregnated carbon composite in the flow cathode creates effective interfaces between the insulating sulphur and conductive carbon-percolating network and offers a promising direction to develop high-energy-density flow batteries.

Multivalent conjugation of antibody to dendrimers for the enhanced capture and regulation on colon cancer cells.

Circulation tumor cells (CTCs) in the bloodstream of early-stage cancer patients carry the important information about valuable biomarkers and biological properties of primary tumor. However, detection and capture of CTCs are challenging owing to their low concentrations. Traditional technologies have the limited detection sensitivity and the low capture efficiency. We, herein, report an effective approach to specifically bind and capture colon cancer HT29 cells by using multiple Sialyl Lewis X antibodies (aSlex)-conjugated PAMAM dendrimers. The conjugation was characterized by using atom force microscope, UV and fluorescence measurements. The capturing and regulating HT29 cells by the aSlex-coated dendrimer conjugate were analyzed by microscopy and flow cytometry. The results indicated that the conjugate showed the enhanced capture of HT29 cells in a concentration-dependent manner and the maximum capture efficiency of 77.88% was obtained within 1 h-exposure. G6-5aSlex-FITC conjugate showed capture efficiency better than FITC-G6-COOH-5aSlex conjugate. G6-5aSlex-FITC conjugate could specifically capture HT29 cells even when the target HT29 cells were diluted with the interfering cells (e.g., RBCs) to a low concentration. The capture resulted in a concentration-dependent restraint of the cell activity. In conclusion, the aSlex-coated dendrimer conjugate displayed the great potential in capturing and restraining colorectal CTCs in blood.