Pathway for high-energy density LiMnFePO4 cathodes

Polyanion cathodes are credited for its thermal stability and better safety, no matter in lithium ion batteries or sodium ion batteries. Polyanion oxides with phosphate groups came to the public's attention in 1997, and the representative material is LiFePO4, which has been widely applied and plays a huge role in the field of powder batteries and energy storage system. However, owing to the low lithiation potentials and storage sites, the energy densities of polyanion cathodes have been restricted, resulting of low-endurance and limited application scenarios. Accordingly, here, we use cheap and environmental friendly raw materials as precursors to synthesis high energy density LiMn0.6Fe0.4PO4@C cathode by a simple spray-drying and high temperature calcination process. The self-designed liquid polyacrylonitrile (LPAN) is added for the intention of nanoparticle coating, conductive network construction and particle granulation. The low-cost and carbon-coated LiMn0.6Fe0.4PO4 cathode exhibits excellent reversible capacity, low electrochemical polarization and excellent rate capacity, which maintains 93.5% capacity retention after cycling 1000 times at 5C. The work introduces a new avenue to fabricate olivine structure cathodes with outstanding electrochemical performance for the high energy density lithium ion batteries

PARP inhibitor veliparib and HDAC inhibitor SAHA synergistically co-target the UHRF1/BRCA1 DNA damage repair complex in prostate cancer cells

Abstract Background The poly ADP ribose polymerase (PARP) inhibitor olaparib has been approved for treating prostate cancer (PCa) with BRCA mutations, and veliparib, another PARP inhibitor, is being tested in clinical trials. However, veliparib only showed a moderate anticancer effect, and combination therapy is required for PCa patients. Histone deacetylase (HDAC) inhibitors have been tested to improve the anticancer efficacy of PARP inhibitors for PCa cells, but the exact mechanisms are still elusive. Methods Several types of PCa cells and prostate epithelial cell line RWPE-1 were treated with veliparib or SAHA alone or in combination. Cell viability or clonogenicity was tested with violet crystal assay; cell apoptosis was detected with Annexin V-FITC/PI staining and flow cytometry, and the cleaved PARP was tested with western blot; DNA damage was evaluated by staining the cells with γH2AX antibody, and the DNA damage foci were observed with a fluorescent microscopy, and the level of γH2AX was tested with western blot; the protein levels of UHRF1 and BRCA1 were measured with western blot or cell immunofluorescent staining, and the interaction of UHRF1 and BRCA1 proteins was detected with co-immunoprecipitation when cells were treated with drugs. The antitumor effect of combinational therapy was validated in DU145 xenograft models. Results PCa cells showed different sensitivity to veliparib or SAHA. Co-administration of both drugs synergistically decreased cell viability and clonogenicity, and synergistically induced cell apoptosis and DNA damage, while had no detectable toxicity to normal prostate epithelial cells. Mechanistically, veliparib or SAHA alone reduced BRCA1 or UHRF1 protein levels, co-treatment with veliparib and SAHA synergistically reduced BRCA1 protein levels by targeting the UHRF1/BRCA1 protein complex, the depletion of UHRF1 resulted in the degradation of BRCA1 protein, while the elevation of UHRF1 impaired co-treatment-reduced BRCA1 protein levels. Co-administration of both drugs synergistically decreased the growth of xenografts. Conclusions Our studies revealed that the synergistic lethality of HDAC and PARP inhibitors resulted from promoting DNA damage and inhibiting HR DNA damage repair pathways, in particular targeting the UHRF1/BRCA1 protein complex. The synergistic lethality of veliparib and SAHA shows great potential for future PCa clinical trials

A Novel Cellular Senescence Gene, <i>SENEX</i>, Is Involved in Peripheral Regulatory T Cells Accumulation in Aged Urinary Bladder Cancer

<div><p>Regulatory T cells (Tregs) play an essential role in sustaining self-tolerance and immune homeostasis. Despite many studies on the correlation between Tregs accumulation and age, or malignancies, the related mechanism hasn’t been well explored. To find out the mechanism of Tregs accumulation in aged urinary bladder cancer, we examined the novel cellular senesence gene <i>SENEX</i> and relevant apoptosis gene mRNA expression in sorted CD4+CD25^hi Tregs from aged UBC donors, evaluated serum cytokine profiles related to tumor immunopathology, and further explored the relationship between <i>SENEX</i> expression, apoptosis gene expression and cytokine secretion. After having silenced down SENEX gene expression with RNA interference, we also evaluated the cellular apoptosis of Tregs sorted from aged UBC patients in response to H₂O₂-mediated stress. Our data indicated that upregulated <i>SENEX</i> mRNA expression in Tregs of aged UBC patients was correlated with pro-apoptotic gene expression and cytokine concentration. Silencing <i>SENEX</i> gene expression increased cellular apoptosis and pro-apoptotic gene expression of Tregs, in response to H₂O₂-mediated stress. Upregulated <i>SENEX</i> mRNA expression together with decreased pro-apoptotic gene expression and disturbances in cytokines synthesis may contribute to the Tregs proliferation and promote tumorigenesis and metastasis. Overall, upregulation of cellular senescence gene <i>SENEX</i>, was associated to regulatory T cells accumulation in aged urinary bladder cancer. Our study provides a new insight into understanding of peripheral Tregs accumulation in aged malignancies.</p></div

Downregulated gene expression of <i>P53</i>, <i>P16</i>, <i>P21</i> and <i>Caspase-3</i> in CD4+CD25^hi Tregs of aged UBC patients.

<p>Tregs were sorted by FACS, mRNA levels were detected by real-time quantitative PCR. In Aged UBC Patiens, apoptosis regulatory genes Caspase-3, P53, P16 and P21 mRNA expression (2^−△△CT = 1183.42±321.17, 15.66±4.83, 23.06±4.59 and 2415.85±863.72, respectively) decreased in Tregs of Aged UBC patients (<i>p</i><0.05 for each Mann-Whitney U Test). Data were expressed as the mean ± SD. ▴ vs. Teffs sorted from Aged UBC patients, P<0.05.</p

Silencing down <i>SENEX</i> gene expression increased Tregs apoptosis in response to H₂O₂-mediated stress in vitro.

<p>Sorted CD4+CD25^high Tregs were stained with Annexin V-FITC before Flow cytometric analysis. Cell apoptosis were detected as Annexin V+ apoptotic cells. 100 µM H₂O₂ treatment for 2 hours increased apoptotic cells in both Tregs (11.2±2.6%) and Teffs (13.1±4.3%), with no significant difference observed in H₂O₂ induced apoptosis between Tregs and Teffs. Silencing down <i>SENEX</i> gene with RNA interference (RNAi) for 24h, follwed by H₂O₂ treatment for 2 hours, increased apoptotic cells in Tregs (21.5±3.4%), but undergoing the same procedures, apoptotic cells wasn’t found to increase in Teffs (13.9±3.1%). No difference was observed in cellular apoptosis between Tregs and Teffs when cells were treated with SiRNA transfection alone.</p

Increased levels of TGF-β1, IL-10, IL-17 and TNF-α serum concentration and decreased levels of IL-2 serum concentration in aged UBC patients.

<p>Expressed as the mean ± SD, data were analyzed with the parametric Student’s T test. ▴ vs. Aged Healthy Controls and Young Healthy Controls, P<0.05; △vs. Young Healthy Controls, P<0.05.</p

Upregulated <i>SENEX</i> mRNA expression in CD4+CD25^hi Tregs sorted from Aged UBC patients.

<p>Tregs were sorted by FACS, <i>SENEX</i> mRNA level was detected by real-time quantitative PCR. An significant increase in <i>SENEX</i> mRNA expression was detected in CD4+CD25^hi Tregs (2^−△△CT = 0.8532±0.1078) as compared to CD4+CD25- Teffs (0.1564±0.0731) in Aged UBC patients (<i>p</i> = 0.027), and this increase was not observed in other groups. Tregs <i>SENEX</i> mRNA expression in Aged UBC patients was signicantly higher than those in Aged Healthy Controls (0.0923±0.0519) and Young Healthy Controls (0.1455±0.0792) (p<0.05 for each Mann-Whitney <i>U</i>-test). Data were expressed as the mean ± SD. ▴ vs. Teffs sorted from Aged UBC patients, P<0.05; △vs. Tregs in Aged Healthy Controls and Young Healthy Controls, P<0.05.</p

Sequences used for Real-time quantitative PCR primers and SiRNA transfection.

<p>Sequences used for Real-time quantitative PCR primers and SiRNA transfection.</p