Metformin prevents the onset and progression of intervertebral disc degeneration: New insights and potential mechanisms (Review).

Metformin has been the go­to medical treatment for addressing type 2 diabetes mellitus (T2DM) as a frontline oral antidiabetic. Obesity, cancer and bone deterioration are linked to T2DM, which is considered a metabolic illness. Numerous diseases associated with T2DM, such as tumours, cardiovascular disease and bone deterioration, may be treated with metformin. Intervertebral disc degeneration (IVDD) is distinguished by degeneration of the spinal disc, accompanied by the gradual depletion of proteoglycans and water in the nucleus pulposus (NP) of the IVD, resulting in lower back pain. The therapeutic effect of metformin on IVDD has also attracted much attention. By stimulating AMP­activated kinase, metformin could enhance autophagy and suppress cell senescence, apoptosis and inflammation, thus effectively delaying IVDD. The present review aimed to systematically explain the development of IVDD and mechanism of metformin in the treatment and prevention of IVDD to provide a reference for the clinical application of metformin as adjuvant therapy in the treatment of IVDD.

Identifying determinants of spatial agglomeration of healthcare resources by using spatial econometric methods: a longitudinal study in China.

Background: Healthcare resources are necessary for individuals to maintain their health. The Chinese government has implemented policies to optimize the allocation of healthcare resources and achieve the goal of equality in healthcare for the Chinese people since the implementation of the new medical reform in 2009. Given that no study has investigated regional differences from the perspective of healthcare resource agglomeration, this study aimed to investigate China's healthcare agglomeration from 2009 to 2017 in China and identify its determinants to provide theoretical evidence for the government to develop and implement scientific and rational healthcare policies. Methods: The study was conducted using 2009-2017 data to analyze health-resource agglomeration on institutions, beds, and workforce in China. An agglomeration index was applied to evaluate the degree of regional differences in healthcare resource allocation, and spatial econometric models were constructed to identify determinants of the spatial agglomeration of healthcare resources. Results: From 2009 to 2017, all the agglomeration indexes of healthcare exhibited a downward trend except for the number of institutions in China. Population density (PD), government health expenditures (GHE), urban resident's disposable income (URDI), geographical location (GL), and urbanization level (UL) all had positive significant effects on the agglomeration of beds, whereas both per capita health expenditures (PCHE), number of college students (NCS), and maternal mortality rate (MMR) had significant negative effects on the agglomeration of institutions, beds, and the workforce. In addition, population density (PD) and per capita gross domestic product (PCGDP) in one province had negative spatial spillover effects on the agglomeration of beds and the workforce in neighboring provinces. However, MMR had a positive spatial spillover effect on the agglomeration of beds and the workforce in those regions. Conclusion: The agglomeration of healthcare resources was observed to remain at an ideal level in China from 2009 to 2017. According to the significant determinants, some corresponding targeted measures for the Chinese government and other developing countries should be fully developed to balance regional disparities in the agglomeration of healthcare resources across administrative regions.

Construction of Successive Proton Conduction Channels to Accelerate the Proton Conduction Process in Flexible Proton Exchange Membranes.

Successive proton conduction channels are constructed with the spin coating method in flexible proton exchange membranes (PEMs). In this research, phosphoric acid (PA) molecules are immobilized in the multilayered microstructure of Kevlar nanofibers and polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene (SEBS) polymer molecular chains. As a result, successive proton conduction channels can accelerate the proton conduction process in the prepared membrane with the multilayered microstructure. Additionally, the microstructure fractures of the composite membranes from the external force of folding and stretching operations are modified by the inner PA molecules. Notably, numerous PA molecules are further combined through formed intermolecular hydrogen bonding. The stretched membrane absorbs more PA molecules owing to the arrangement of PA molecules, Kevlar nanofibers, and SEBS molecular chains. The stretched membrane thus exhibits the enhanced proton conduction ability, such as the through-plane proton conductivity of 1.81 × 10-1 S cm-1 at 160 °C and that of 4.53 × 10-2 S cm-1 at 120 °C lasting for 600 h. Furthermore, the tensile stress of PA-doped stretched membranes reaches (3.91 ± 0.40)-(6.15 ± 0.43) MPa. A single proton exchange membrane fuel cell exhibits a peak power density of 483.3 mW cm-2 at 120 °C.

Diatom-dinoflagellate succession in the Bohai Sea: The role of N/P ratios and dissolved organic nitrogen components.

Dissolved organic nitrogen (DON) is a pivotal component of total dissolved nitrogen pools, serving as a crucial nitrogen source for phytoplankton. This study investigated the impact of nitrogen-to-phosphorus (N/P) ratios and different DON components (hydrophilic vs hydrophobic DON) on diatom-dinoflagellate succession through field culture experiments. Results showed that dinoflagellates have a competitive advantage under high N/P ratios and phosphorus limitation, regardless of DON or DIN treatments. Hydrophilic DON exhibits greater bioavailability than hydrophobic DON (40.6% vs. 21.7 %), resulting in increased algal biomass and diatoms dominance in the community. Additionally, DON was categorized into labile and refractory components (LDON and RDON) based on bioavailability. LDON primarily consists of protein-like components that can be readily consumed by algae, whereas RDON is primarily composed of humic-like components that are less accessible to algae. Diatoms and dinoflagellates exhibited differential responses to LDON and RDON, with diatoms thriving in high LDON environments, while dinoflagellates gained a competitive advantage when RDON was the predominant nitrogen source. Furthermore, a significant negative correlation was observed between bioavailable nitrogen concentration (BAN: DIN + LDON) and the ratio of dinoflagellates to diatoms (p<0.05). In conclusion, our study highlights the role of LDON in promoting diatom dominance, whereas environments dominated by RDON foster dinoflagellate success. These findings enhance our comprehension of diatom-dinoflagellate succession dynamics.

Physiological Effects of Co-exposure to Ionizing Radiation and Noise within Occupational Exposure Limits.

ABSTRACT: Workers are frequently exposed to the occupational hazards of ionizing radiation and noise. Co-exposure to these hazards is not well understood in terms of their physiological effects. The aim of this study was to investigate the physiological effects of co-exposure to ionizing radiation and noise within the occupational limit. This study extracted the physical examination parameters of workers who met the screening criteria from the occupational health surveillance database. The workers were divided into three groups: the co-exposure (COE) group, the ionizing radiation exposure (ION) group, and the non-exposure (NON) group. The age and sex of the three groups were matched with a sample size ratio of 1:3:3. The physical examination parameters of the three groups of workers were compared. The results showed that there was no significant difference in blood pressure and blood biochemical parameters among the three groups. The COE group had higher levels of free triiodothyronine than the ION group, but there was no difference with the NON group. Moreover, the COE group had lower levels of free tetraiodothyronine than the ION group and the NON group. There was no significant difference in thyroid stimulating hormone, total triiodothyronine, and total tetraiodothyronine among the three groups. Additionally, the number of white blood cells of the COE group was lower than that of ION group and NON group. This study suggests that co-exposure to low-dose ionizing radiation and noise can cause alterations in thyroid hormone and peripheral white blood cells. These alterations are different from those observed after single exposure to low-dose ionizing radiation and require further research.

Caffeic acid phenethyl ester surmounts acquired resistance of AZD9291 in non-small cell lung cancer cells.

Epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first-line therapy for EGFR mutated non-small cell lung cancer (NSCLC); however, resistance rapidly develops. The objective of this study was therefore to establish and characterize a gefitinib resistant NSCLC line (HCC827GR) and evaluate the therapeutic effects of natural products in combination with third-generation EGFR-TKI, AZD9291. The IC50 of gefitinib and AZD9291 in HCC827GR were significantly higher than those of HCC827 (p < 0.05). Furthermore, anchorage-independent colony assay indicated that HCC827GR cells were more aggressive than their predecessors. This was reflected by the gene/protein expression changes observed in HCC827GR versus HCC827 profiled by cancer drug resistance real-time polymerase chain reaction (RT-PCR) array and Western blot. Three natural products were screened and caffeic acid phenethyl ester (CAPE) exhibited the most significant combinative cytotoxic effect with AZD9291. Specifically, flow cytometry revealed that AZD9291 + CAPE considerably increased the fraction of cell in pre-G1 of the cell cycle and caspase-Glo3/7 assay showed a dramatic increase in apoptosis when compared to AZD9291 alone. Furthermore, Western blot showed significant downregulation of p-EGFR/p-AKT in HCC827GR cells treated with AZD9291 + CAPE as compared to AZD9291. Moreover, it is evident that AZD9291 + CAPE specifically resulted in a marked reduction in the protein expressions of the cell-proliferation-related genes p21, cyclin D1, and survivin. Finally, refined RT-PCR/Western blot data indicated that AZD9291 + CAPE may at least partially exert its synergistic effects via the PLK2 pathway. Together, these results suggest that CAPE is a clinically relevant compound to aid AZD9291 in treating EGFR-TKI resistant cells through modulating critical genes/proteins involved in cancer resistance/therapy.

Measuring the inequalities in healthcare resource in facility and workforce: A longitudinal study in China.

Objective: The study aimed to measure time trends of inequalities of the geographical distribution of health facilities and workforce in Shanghai from 2010 to 2016 and used a spatial autocorrelation analysis method to precisely detect the priority areas for optimizing health resource reallocation in metropolises like Shanghai in developing countries. Methods: The study used secondary data from the Shanghai Health Statistical Yearbook and the Shanghai Statistical Yearbook from 2011 to 2017. Five indicators on health resources, namely, health institutions, beds, technicians, doctors, and nurses, were employed to quantitatively measure the healthcare resource in Shanghai. The Theil index and the Gini coefficient were applied to assess the global inequalities in the geographic distribution of these resources in Shanghai. Global and local spatial autocorrelation was performed using global Moran's index and local Moran's index to illustrate the spatial changing patterns and identify the priority areas for two types of healthcare resource allocation. Results: Shanghai's healthcare resources showed decreasing trends of inequalities at large from 2010 to 2016. However, there still existed an unchanged over-concentration distribution in healthcare facilities and workforce density among districts in Shanghai, especially for doctors at the municipal level and facility allocation at the rural level. Through spatial autocorrelation analysis, it was found that there exhibited a significant spatial autocorrelation in the density distribution of all resources, and some identified priority areas were detected for resource re-allocation policy planning. Conclusion: The study identified the existence of inequality in some healthcare resource allocations in Shanghai from 2010 to 2016. Hence, more detailed area-specific healthcare resource planning and distribution policies are required to balance the health workforce distribution at the municipal level and institution distribution at the rural level, and particular geographical areas (low-low and low-high cluster areas) should be focused on and fully considered across all the policies and regional cooperation to ensure health equality for municipal cities like Shanghai in developing countries.

Antimicrobial indole alkaloids from Tabernaemontana corymbosa.

Four unreported monoterpene indole alkaloids, tabernaecorymines B-E (1-4), together with twenty-one known indole alkaloids (5-25) were obtained from the stem bark of Tabernaemontana corymbosa. Their structures and absolute configurations were elucidated by extensive spectroscopy, quantum chemical calculations, DP4+ probability analyses and Mo2(OAc)4-induced electronic circular dichroism experiment. The antibacterial and antifungal activities of these compounds were evaluated and some of them showed significant activity against Staphylococcus aureus,Bacillus subtilis, Streptococcus dysgalactiae and Candida albicans.

Pepsin enhances glycolysis to promote malignant transformation of vocal fold leukoplakia epithelial cells with dysplasia.

PURPOSE: The mechanism underlying malignant transformation of vocal fold leukoplakia (VFL) and the precise role of the expression of pepsin in VFL remain unclear. This study aimed to investigate the effects of acidified pepsin on VFL epithelial cell growth and migration, and also identify pertinent molecular mechanisms. METHODS: Immunochemistry and Western blotting were performed to measure glucose transporter type 1 (GLUT1), monocarboxylate transporters 4 (MCT4), and Hexokinase-II (HK-II) expressions. Cell viability, cell cycle, apoptosis, and migration were investigated by CCK-8 assay, flow cytometry and Transwell chamber assay, respectively. Glycolysis-related contents were determined using the corresponding kits. Mitochondrial HK-II was photographed under a confocal microscope using Mito-Tracker Red. RESULTS: It was found: the expression of pepsin and proportion of pepsin+ cells in VFL increased with the increased dysplasia grade; acidified pepsin enhanced cell growth and migration capabilities of VFL epithelial cells, reduced mitochondrial respiratory chain complex I activity and oxidative phosphorylation, and enhanced aerobic glycolysis and GLUT1 expression in VFL epithelial cells; along with the transfection of GLUT1 overexpression plasmid, 18FFDG uptake, lactate secretion and growth and migration capabilities of VFL epithelial cell were increased; this effect was partially blocked by the glycolysis inhibitor 2-deoxy-glucose; acidified pepsin increased the expression of HK-II and enhanced its distribution in mitochondria of VFL epithelial cells. CONCLUSION: It was concluded that acidified pepsin enhances VFL epithelial cell growth and migration abilities by reducing mitochondrial respiratory complex I activity and promoting metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis.

Proteome derangement in malignant epithelial cells and its stroma following exposure to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

Discovering novel changes in the proteome of malignant lung epithelial cells and/or the tumor-microenvironment is paramount for diagnostic, prognostic, and/or therapy development. A time-dependent 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mouse lung tumor model was used to screen the proteome of lung tumors. NNK-transformed human lung epithelial BEAS-2B cells were then established to evaluate the epithelial cell-specific protein changes. A duration-dependent increase of tumor burden was observed in NNK-treated mice, 2/12 (17%), 8/12 (67%), 9/12 (75%), and 10/10 (100%) at weeks 8, 12, 16, and 20 after the NNK exposure, respectively. A total of 25 differentially expressed proteins (≥ twofold change), predominantly structural, signaling, and metabolic proteins, were detected by two-dimensional difference gel electrophoresis and identified by mass spectrometry. Calregulin, ezrin, histamine releasing factor (HRF), and inorganic pyrophosphatase 1 (PPA1) exhibited changes and were further confirmed via immunoblotting. In addition, immunohistochemistry (IHC) analysis indicated upregulated E-cadherin and decreased vimentin expression in epithelial cells of tumor tissues. Acquisition of a neoplastic phenotype in NNK-transformed BEAS-2B cells was demonstrated by enhanced wound closure and increased anchorage independent colony formation. In transformed BEAS-2B cells, protein expression of E-cadherin, ezrin, and PPA1 (but not calregulin and HRF) was upregulated, as was observed in tumor tissues IHC staining using mouse lung tumor tissues further revealed that HRF upregulation was not lung epithelial cell specific. Altogether, tumorigenesis after NNK exposure may be initiated by protein dysregulation in lung epithelial cells together with proteome derangement derived from other cell types existing in the tumor-microenvironment.

Effect of dissolved organic nutrients on the bloom of Prorocentrum donghaiense in the East China Sea coastal waters.

Prorocentrum donghaiense blooms occur annually in the East China Sea coastal waters, degrading ecosystem functions and impeding economic development. Dissolved organic nitrogen and phosphorus (DON and DOP) are the main components in the marine nutrient pools and are closely related to harmful algal blooms. From April to June 2019, a survey was conducted along the East China Sea coast (Sansha and Lianjiang counties) to investigate the relationship between dissolved organic nutrients and P. donghaiense bloom. Our findings showed that dinoflagellates dominated the phytoplankton community, and dissolved organic nutrients were the major factors influencing community structure during the P. donghaiense bloom. Redundancy analysis indicated that P. donghaiense abundance was primarily affected by DON in the Sansha area while it was primarily affected by DON and DOP in the Lianjiang area. Correlation analysis also confirmed a strong positive correlation between dissolved organic nutrients and P. donghaiense abundance both in the Sansha and Lianjiang coastal areas (p < 0.001). Furthermore, a culture experiment was carried out during the bloom to further investigate the effect of dissolved organic nutrients on the phytoplankton community structure. After 10 days of culture, dinoflagellates' relative abundance decreased from 97.1% to 28.2% in the inorganic treatment, whereas dinoflagellates continued to dominate the phytoplankton community in the organic treatment (76.9%). As a result, we propose that dissolved organic nutrients are responsible for the P. donghaiense bloom outbreak and promote the phytoplankton community shift from diatoms to dinoflagellates.

Comparative Microbiomics Analysis of Antimicrobial Antibody Response between Patients with Lung Cancer and Control Subjects with Benign Pulmonary Nodules.

BACKGROUND: CT screening can detect lung cancer early but suffers a high false-positive rate. There is a need for molecular biomarkers that can distinguish malignant and benign indeterminate pulmonary nodules (IPN) detected by CT scan. METHODS: We profiled antibodies against 901 individual microbial antigens from 27 bacteria and 29 viruses in sera from 127 lung adenocarcinoma (ADC), 123 smoker controls (SMC), 170 benign nodule controls (BNC) individuals using protein microarrays to identify ADC and BNC specific antimicrobial antibodies. RESULTS: Analyzing fourth quartile ORs, we found more antibodies with higher prevalence in the three BNC subgroups than in ADC or SMC. We demonstrated that significantly more anti-Helicobacter pylori antibodies showed higher prevalence in ADC relative to SMC. We performed subgroup analysis and found that more antibodies with higher prevalence in light smokers (≤20 pack-years) compared with heavy smokers (>20 pack-years), in BNC with nodule size >1 cm than in those with ≤1 cm nodules, and in stage I ADC than in stage II and III ADC. We performed multivariate analysis and constructed antibody panels that can distinguish ADC versus SMC and ADC versus BNC with area under the ROC curve (AUC) of 0.88 and 0.80, respectively. CONCLUSIONS: Antimicrobial antibodies have the potential to reduce the false positive rate of CT screening and provide interesting insight in lung cancer development. IMPACT: Microbial infection plays an important role in lung cancer development and the formation of benign pulmonary nodules.

Acrylamide-induced damage to postsynaptic plasticity is CYP2E1 dependent in an SH-SY5Y co-culture system.

Acrylamide (ACR), a neurotoxic substance, is characterized by a range of industrial and population exposures. The effects of ACR on synapses have been examined, but the regulation and molecular mechanism of key proteins related to ACR and its metabolite glycidamide (GA) have not been elucidated. In this study, we constructed two co-culture systems to mimic neurons that do not express and overexpress CYP2E1. In these co-cultures, we observed the effects and relative influence of ACR and GA on cell survival as well as synaptic structural and functional plasticity. Next, we investigated the relationship between ACR-induced nerve damage and key proteins in the postsynaptic membrane. After ACR exposure, cell death and synaptic damage were significantly worse in CYP2E1-overexpressing co-culture systems, suggesting that ACR-induced neurotoxicity may be related to metabolic efficiency (including CYP2E1 activity). Moreover, with increasing doses of ACR, the key postsynaptic membrane proteins PSD-95 expression was reduced and CaMKII and NMDAR-2B phosphorylation was increased. ACR exposure also triggered a rapid dose- and time-dependent increase in intracellular Ca2+, whose changes can affect the expression of the above-mentioned key proteins. In summary, we clarified the relationship between ACR exposure, neuronal damage and postsynaptic plasticity and proposed an ACR-CYP2E1-GA: Ca2+-PSD-95-NMDAR-Ca2+-CaMKII effect chain. This information will further improve the development of an alternative pathway strategy for investigating the risk posed by ACR.

Biomarkers of exposure and effect in the serum and urine of rats or workers exposed to 1-bromopropane.

Extensively used in several industries in China as a cleaning agent, 1-bromopropane (1-BP) has significant adverse effects on the central nervous system. However, neither its mechanism of action nor sensitive biomarkers related to it have been determined thus far. In this study, animal experiments and occupational surveys were performed to explore the typical exposure and effect biomarkers of neurotoxicity induced by 1-BP. Male Wistar rats were exposed to 0, 500, or 1000 ppm of 1-BP followed by pathological and biomarker analyses. An epidemiological survey was conducted on 71 workers each from 1-BP exposed and control groups. Serum and urine samples were collected for biomarker testing. cNSE represents neuron-specific enolase (NSE) in the cerebral cortex, where as sNSE represents NSE in the serum; similar terminology applies to S-100ß, and cyclooxygenase-2 (COX-2). In rats exposed to 1000 ppm 1-BP, pathological changes were observed in Purkinje cells, lumbar gray matter, and tibiofibular nerve, while levels of cNSE, cS-100ß, cCOX-2, sS-100ß, and sCOX-2 were significantly elevated at different time checkpoints. In the 500 ppm group, cCOX-2, sNSE, and sCOX-2 levels were significantly elevated at different time checkpoints. 1-BP and N-acetyl-S-(n-propyl)-L-cysteine (AcPrCys) were detected in rat urine, and there was a correlation between the level of sNSE or sCOX-2 and AcPrCys in the 500 ppm group. In the occupational epidemiological study, a significant correlation between AcPrCys and exposure concentration was also detected. The findings of this study indicated that AcPrCys was a sensitive exposure biomarker of 1-BP in rats as well as occupational populations.

In situ observation of the electrochemical lithiation of a single MnO@C nanorod electrode with core/shell structure.

Transition metal oxides (TMOs) play a crucial role in lithium-ion batteries (LIBs) due to their high theoretical capacity, natural abundance, and benign environmental impact, but they suffer from limitations such as cyclability and high-rate discharge ability. One leading cause is the lithiation-induced volume expansion (LIVE) for "conversion"-type TMOs, which can result in high stress, fracture and pulverization. Using carbon layers is an effective strategy to provide effective volumetric accommodation for lithium-ion (Li+) insertion; however, the detailed mechanism is unknown. In order to clarify the working mechanism of nanoscale LIBs, herein, the discharge reactions in a nanoscale LIB were investigated through in situ environmental transmission electron microscopy (ETEM). Visualization of the Li+ insertion process of MnO@C nanorods (NRs) with core/shell structure (CSS) and internal void space (IVS) was achieved. The LIVE occurred in a consecutive two-step mode, i.e., a LIVE of the carbon layer followed by a co-LIVE of the carbon layer and MnO. No volume contraction of the IVS was observed. The IVS acted as a buffer relieving the stress of the carbon layer. The carbon layer with IVS simultaneously improved the cyclability and the high-rate discharge ability of the electrode, pointing to a promising route for building better TMO electrode materials.

Controlling phase and rheological behaviours of hexagonal lyotropic liquid crystalline templates for nanostructural administration and retention.

Introducing polymerizable monomers into a binary hexagonal lyotropic liquid crystalline (LLC) template is a straightforward way for retaining the nanostructure but will decrease attractive intra- and inter- aggregate interactions. It is therefore crucial to understand the interfacial interactions at nanoscale after introducing the monomers but prior to polymerization. Herein, active species, poly (ethylene glycol) diacrylate (PEGDA) and 2-hydroxyethyl methacrylate (HEMA), were introduced into hexagonal LLC of dodecyl trimethylammonium bromide and water to explore the structural variables, dimensional stability, and dynamic property. At a proper volume ratio of PEGDA/HEMA (1/4), the system presents excellent homogeneity with a higher dimensional stability and lower dynamic property from rheological assessments, thereby achieving robust, free-standing, and transparent membranes after photo-polymerization. The unique property of the system also lies in the much lower order-disorder transition temperature (45 °C) that facilitates the reorientation of mesochannels. They are in contrast inaccessible for the ternary system only with PEGDA, though the nanostructure for both systems could be retained. An insight into subtle variations in these parameters allows us to prepare a polymerizable template possessing higher dimensional stability and suitable flexibility via molecular design, thereby enabling simultaneous structural alignment and retention for the development of functional nanomaterials.

In Situ-Grown Heterostructured Co3S4/CNTs/C Nanocomposites with a Bridged Structure for High-Performance Supercapacitors.

As one of the most competitive candidates for energy storage devices, supercapacitors have attracted extensive research interest due to their incomparable power density and ultralong cycling stability. However, the large surface area required for charge storage is an irreconcilable contradiction with the requirement of energy density. Therefore, a high energy density is a major challenge for supercapacitors. To solve the contradiction, Co3S4/CNTs/C with a bridged structure is designed, where CNTs generated in situ serve as a bridge to connect a porous carbon matrix and a Co3S4 nanoparticle, and Co3S4 nanoparticles are anchored on the topmost of CNTs. The porous carbon and Co3S4 are used for electrochemical double-layer capacitors and pseudocapacitors, respectively. This bridged structure can efficiently utilize the surface of Co3S4 nanoparticles to increase the overall energy storage capacity and provide more electrochemically active sites for charge storage and delivery. The materials show an energy density of 41.3 Wh kg-1 at 691.9 W kg-1 power density and a retaining energy density of 33.1 Wh kg-1 at a high power density of 3199.9 W kg-1 in an asymmetrical supercapacitor. The synthetic technique provides a simple method to obtain heterostructured nanocomposites with a high energy density by maximizing the effect of pseudocapacitor electrode active materials.

Overcoming the acquired resistance to gefitinib in lung cancer brain metastasis in vitro and in vivo.

In our previous work, PC-9-Br, a PC-9 brain seeking line established via a preclinical animal model of lung cancer brain metastasis (LCBM), exhibited not only resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib in vitro, but also chemotherapy regimens of cisplatin plus etoposide in vivo. Using this cell line, we investigated novel potential targeted therapeutics for treating LCBM in vitro and in vivo to combat drug resistance. Significant increases in mRNA and protein expression levels of Bcl-2 were found in PC-9-Br compared with parental PC-9 (PC-9-P), but no significant changes of Bcl-XL were observed. A remarkable synergistic effect between EGFR-TKI gefitinib and Bcl-2 inhibitors ABT-263 (0.17 ± 0.010 µM at 48 h and 0.02 ± 0.004 µM at 72 h), or ABT-199 (0.22 ± 0.008 µM at 48 h and 0.02 ± 0.001 µM at 72 h) to overcome acquired resistance to gefitinib (> 0.5 µM at 48 h and 0.10 ± 0.007 µM at 72 h) in PC-9-Br was observed in MTT assays. AZD9291 was also shown to overcome acquired resistance to gefitinib in PC-9-Br in MTT assays (0.23 ± 0.031 µM at 48 h and 0.03 ± 0.008 µM at 72 h). Western blot showed significantly decreased phospho-Erk1/2 and increased cleaved-caspase-3 expressions were potential synergistic mechanisms for gefitinib + ABT263/ABT199 in PC-9-Br. Significantly decreased protein expressions of phospho-EGFR, phospho-Akt, p21, and survivin were specific synergistic mechanism for gefitinib + ABT199 in PC-9-Br. In vivo studies demonstrated afatinib (30 mg/kg) and AZD9291 (25 mg/kg) could significantly reduce the LCBM in vivo and increase survival percentages of treated mice compared with mice treated with vehicle and gefitinib (6.25 mg/kg). In conclusion, our study demonstrated gefitinib + ABT263/ABT199, afatinib, and AZD9291 have clinical potential to treat LCBM.