Acid Sphingomyelinase Regulates the Localization and Trafficking of Palmitoylated Proteins

In human, loss of Acid Sphingomeylinase (ASM/SMPD1) causes Niemann-Pick Disease, type A. ASM hydrolyzes sphingomyelins to produce ceramides but protein targets of ASM remain largely unclear. ... See full text for complete abstract

Effect of sodium butyrate on glucose and lipid metabolism, insulin expression and apoptosis of β-cells in obese pregnant rats

Purpose: To study the influence of sodium butyrate on the metabolism of lipid and glucose, insulin expression and apoptosis of β-cells in obese pregnant rats. Methods: Three groups of one hundred and twenty 4-week-old female C5BL/6J mice were used: control, high-fat diet and sodium butyrate groups. Insulin, triglycerides and total cholesterol were evaluated by enzyme-linked immunosorbent assay (ELISA). Insulin levels, as well as area and quality of islet β-cells were assessed using Image Pro Plus software. The number of DAPI-positive islet cells, positive expression of bcl-2 in each islet cell, and apoptosis of islet β-cells in each group were determined. Results: The expression levels of insulin in high-fat diet group and butyrate group were significantly reduced, relative to control, but insulin expression level in Na butyrate group increased, relative to high- fat diet mice (p < 0.01). The area and quality of islet β-cells in high-fat diet and sodium butyrate groups were markedly higher in sodium butyrate group than in high-fat diet group (p < 0.01). The bcl-2 expression in islet β-cells rose in mice given high-fat diet, relative to control and sodium butyrate groups (p < 0.01). Conclusion: Sodium butyrate facilitates glucose and lipid metabolism, but increases insulin expression, and effectively inhibits apoptosis of islet β-cells in obese pregnant mice. Thus, sodium butyrate may be useful in the prevention and treatment of metabolic disorders due to diabetes mellitus (DM)

Targeting Radioresistant Breast Cancer Cells by Single Agent CHK1 Inhibitor via Enhancing Replication Stress

Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells

Targeting Radioresistant Breast Cancer Cells by Single Agent CHK1 Inhibitor via Enhancing Replication Stress

Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells

Novel Catalytic Cathode Nanomaterials and Mechanistic Studies for Advanced Lithium–Oxygen Batteries

Since 1996, lithium–oxygen (Li–O2) batteries have been intensively studied as one of the most promising energy storage systems for high-energy applications such as electric vehicles. However, like many emerging technologies, Li–O2 batteries still suffer from several challenges, including high overpotential, poor rate capability, and short cycle life. These shortcomings are mainly caused by the (ⅰ) transport limitations of insoluble discharge products and (ⅱ) parasitic reactions between cathodes/electrolytes and reactive oxygen species. To address these issues, many research efforts have been devoted to promoting the solubility of reaction intermediates in electrolytes via additives and finding alternative chemistries that are less reactive toward cell components than conventional lithium peroxide chemistry. This dissertation describes high-performance Li–O2 batteries that can operate in humid environments via advanced lithium hydroxide (LiOH) chemistry. Benefiting from the tunable structure of metal–organic frameworks (MOFs), we designed and prepared two isoreticular MOF-74 nanomaterials for oxygen cathodes, one with and the other without redox-active metal centers (Mn-MOF-74 and Zn-MOF-74, respectively). We demonstrated that LiOH formed in the presence of moisture via chemical catalysis at coordinatively unsaturated metal centers of Mn-MOF-74.\n To further elucidate the reversibility and reaction mechanisms of LiOH chemistry, we performed a combined experimental and theoretical study. Although LiOH chemistry exhibited excellent cycling and rate performance, systematic characterization studies revealed that LiOH chemistry is irreversible in conventional liquid organic electrolytes using operando cell pressure measurements, isotope labeled mass spectrometry, Fourier-transform infrared (FTIR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. This irreversibility is mainly due to the formation of highly reactive oxygen species that attack organic electrolytes.\n Finally, an outlook for achieving reversible LiOH chemistry is provided, such as using solid-state reactions and redox mediators. Considering that moisture is inevitably present in air, the deep understanding of LiOH chemistry in this dissertation provides insights into practical Li–O2 batteries and other metal–O2 batteries, such as sodium–O2 and potassium–O2 batteries, which can potentially operate in ambient air. Besides, the MOF-based nanomaterials developed in this dissertation might be applied as electrode materials in other energy-related fields, including Li–sulfur batteries and supercapacitors

A convergent fabrication of programmed pH/reduction-responsive nanoparticles for efficient dual anticancer drugs delivery for ovarian cancer treatment

AbstractA nanoparticle-based drug delivery technology could develop combination cancer therapy more effectively. However, because of inadequate drug delivery into tumor cells, the cancer therapeutic efficiency of nanomedicines is diminished. PEGylated poly(α-lipoic acid) copolymers with (mPEG-PLA) were fabricated and used as pH/reductive responsive nanovesicles to administer Gefitinib (GFT) and doxorubicin (DOX) for the treatment of ovarian cancer. The amphiphilic polymers mPEG-PLA may be efficiently incorporated on DOX and GFT to fabricate DOX and GFT coloaded nanoparticles (DOX@GFT-NPs) and self-assembled into an aqueous solution. The DOX@GFT-NPs released more DOX and GFT after being prepared to respond to pH and reduction stimuli. The outcomes of confocal laser scanning microscopy and flow cytometry findings, the SKOV3 ovarian cancer cells quickly fascinated the dual drugs-coloaded nanoparticles and drugs released intracellularly accumulated. DOX@GFT-NPs triggered cell death and demonstrated synergistic therapeutic benefits in SKOV3 cells. Results showed that the nanoparticles efficiently trigger apoptosis in SKOV3 ovarian cancer cells using morphological staining (acridine orange/ethidium bromide (AO/EB) and HOECHST 33342 nuclear staining). These outcomes show that using pH and reduction stimuli on mPEG-PLA copolymer to treat ovarian cancer is a promising approach

Towards High-Performance Metal-Organic-Framework-Based Solid-State Electrolytes: Tunable Structures and Electrochemical Properties

Metal–organic frameworks (MOFs) have been reported as promising solid-state electrolytes owing to their tunable porous structures and ion-sieving capability. However, it remains challenging to rationally design high-performance MOF electrolytes. Herein, we controllably synthesized a series of MOFs to study the effects of pore apertures and open metal sites on ion-transport properties and electrochemical stability of MOF electrolytes. We demonstrate that MOFs with non-redox-active metal centers can lead to a wider electrochemical stability window than those with redox-active centers. Pore aperture of MOFs dominates the uptake of lithium salt and thus ionic conductivity. Ab initio molecular dynamics simulations further demonstrate that open metal sites of MOFs can immobilize anions of lithium salt via Lewis acid–base interaction, leading to a high lithium-ion transference number. This work provides not only a platform for studying ion-transport properties in tunable MOF electrolytes, but also a design strategy for MOF electrolytes with the guide of structure–property relationships

Morphology and Optical Property of ZnO Nanostructures Grown by Solvothermal Method: Effect of the Solution Pretreatment

Zinc oxide (ZnO) nanostructures with different morphologies such as nanopyramids, nanosheets, and nanoparticles have been grown by a simple solvothermal method. The influence of solution pretreatmentt on the morphology and optical properties of ZnO nanostructures has been studied. The experimental results revealed the morphology of ZnO transformed from nanopyramids or nanosheets to nanoparticles after solution pretreatment. Raman and photoluminescence spectra are recorded to examine the crystallinity and optical property of the samples