Muscle mass and plasma myostatin after exercise training: a substudy of Renal Exercise (RENEXC)-a randomized controlled trial.

BACKGROUND: Sarcopenia increases as renal function declines and is associated with higher morbidity and mortality. Myostatin is a negative regulator of muscle growth. Its expression in response to exercise is unclear. In this prespecified substudy of the Renal Exercise (RENEXC) trial, we investigated the effects of 12 months of exercise training on sarcopenia, muscle mass and plasma myostatin and the relationships between physical performance, muscle mass and plasma myostatin. METHODS: A total of 151 non-dialysis-dependent patients (average measured glomerular filtration rate 23 ± 8 mL/min/1.73 m2), irrespective of age or comorbidity, were randomly assigned to either strength or balance in combination with endurance training. Body composition was measured with dual-energy X-ray absorptiometry. Plasma myostatin was analysed using enzyme-linked immunosorbent assay kits. RESULTS: After 12 months, the prevalence of sarcopenia was unchanged, leg and whole-body lean mass increased significantly in the balance group and was unchanged in the strength group. Whole fat mass decreased significantly in both groups. There were no significant between-group differences in sarcopenia or body composition. Plasma myostatin levels increased significantly in both groups, with a significant difference in favour of the strength group. Plasma myostatin was significantly positively related to muscle mass and physical performance at baseline, but these relationships were attenuated after 12 months. CONCLUSIONS: Exercise training seems to be effective in preventing sarcopenia and maintaining muscle mass in non-dialysis-dependent patients with chronic kidney disease (CKD). However, the role of plasma myostatin on muscle mass and physical performance in patients with CKD warrants further study.

Twelve months of exercise training did not halt abdominal aortic calcification in patients with CKD - a sub-study of RENEXC-a randomized controlled trial.

BACKGROUND: Arteriosclerosis is prevalent in patients with chronic kidney disease (CKD). Our aims were to investigate (1) the effects of 12 months of either balance- or strength- both in combination with endurance training on abdominal aortic calcification (AAC); on some lipids and calcific- and inflammatory markers; and (2) the relationships between the change in AAC score and these markers in non-dialysis dependent patients with CKD stages 3 to 5. METHODS: One hundred twelve patients (mean age 67 ± 13 years), who completed 12 months of exercise training; comprising either balance- or strength training, both in combination with endurance training; with a measured glomerular filtration rate (mGFR) 22.6 ± 8 mL/min/1.73m2, were included in this study. AAC was evaluated with lateral lumbar X-ray using the scoring system described by Kauppila. Plasma fetuin-A, fibroblast growth factor 23 (FGF23) and interleukin 6 (IL6) were measured with Enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: After 12 months of exercise training, the AAC score increased significantly in both groups; mGFR and lipoprotein (a) decreased significantly in both groups; parathyroid hormone (PTH) and 1,25(OH)2D3 increased significantly only in the strength group; fetuin-A increased significantly only in the balance group. Plasma triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, FGF23, phosphate, calcium, IL6, C-reactive protein (CRP), albumin were unchanged. The increase in AAC score was positively related to ageing and the levels of baseline triglycerides and lipoprotein (a). CONCLUSIONS: Exercise training did not prevent the progression of AAC; it might have contributed to the reduced levels of lipoprotein (a) and unchanged levels of calcific- and inflammatory markers in these patients with non-dialysis dependent CKD. Hypertriglyceridemia, high levels of lipoprotein (a) and ageing emerged as longitudinal predictors of vascular calcification in these patients. TRIAL REGISTRATION: NCT02041156 at www.ClinicalTrials.gov. Date of registration: January 20, 2014. Retrospectively registered.

Second-Sphere Polyhedron-Distortion-Induced Broadened and Red-Shifted Emission in Lu3(MgxAl2-x)(Al3-xSix)O12:Ce3+ for Warm WLED.

Orange-yellow phosphors with extended broadband emission are highly desirable for warmer white-light-emitting diodes (WLED) with a higher color-rendering index. Targeted phosphors Ce3+-doped Lu3(MgxAl2-x)(Al3-xSix)O12 (x = 0, 0.25, 0.50, 0.75, and 1.00) were developed by chemical composition modification for luminescent tuning from green to orange-yellow with spectral broadening. The correlation between structure evolution and luminescent properties was elucidated by the local structure, fluorescence lifetime, and Eu3+ luminescence as a structural probe. The polyhedron distortion in the second-sphere coordination leads to the site differentiation and symmetry degradation of Ce3+ with the accommodation of (MgSi)6+ pairs, comprehensively resulting in the red shift (540 → 564 nm) and broadening in emission spectra. The WLED fabrication results demonstrate that the red shift and broadening in the emission of Lu3(MgxAl2-x)(Al3-xSix)O12:Ce3+ make it more suitable for the single-phosphor converted warm WLED.

Cyan-Green Phosphor (Lu2M)(Al4Si)O12:Ce3+ for High-Quality LED Lamp: Tunable Photoluminescence Properties and Enhanced Thermal Stability.

High-quality white light-emitting diodes (w-LEDs) are mainly determined by conversion phosphors and the enhancement of cyan component that dominates the high color rendering index. New phosphors (Lu2M)(Al4Si)O12:Ce3+ (M = Mg, Ca, Sr and Ba), showing a cyan-green emission, have been achieved via the co-substitution of Lu3+-Al3+ by M2+-Si4+ pair in Lu3Al5O12:Ce3+ to compensate for the lack of cyan region and avoid using multiple phosphors. The excitation bands of (Lu2M)(Al4Si)O12:Ce3+ (M = Mg, Ca, Sr and Ba) show a red-shift from 434 to 445 nm which is attributed to the larger centroid shift and crystal field splitting. The enhanced structural rigidity associated with the accommodation of larger M2+ leads to a decreasing Stokes shift and the corresponding blue-shift (533 → 511 nm) in emission spectra, along with an improvement in thermal stability (keeping ∼93% at 150 °C). The cyan-green phosphor Lu2BaAl4SiO12:Ce3+ enables to fabricate a superhigh color rendering w-LED ( Ra = 96.6), verifying its superiority and application prospect in high-quality solid-state lightings.

Comparison of DEXA and Bioimpedance for Body Composition Measurements in Nondialysis Patients With CKD.

OBJECTIVES: The aims of this study are (1) to compare dual-energy X-ray absorptiometry (DEXA) and bioimpedance for body composition measurements in nondialysis patients with chronic kidney disease, and (2) to investigate factors associated with any measurement differences. DESIGN AND METHODS: This is a substudy using some baseline data from a randomized controlled clinical trial. One hundred twenty patients (aged 65 ± 14 years) with a measured glomerular filtration rate 8 to 55 mL/min/1.73m2, not on renal replacement therapy, irrespective of age and number of comorbidities, were included from 2011 to 2016. For DEXA measurements, Lunar Prodigy or Lunar iDXA were used. For bioimpedance measurements, body composition monitor (BCM) was used. Glomerular filtration rate was measured with iohexol clearance. Data were analyzed using R software. Bland-Altman analysis was performed to compare the 2 measurements. The measurement difference was DEXA minus BCM. Multiple linear regression analysis was performed to analyze relationships between variables. RESULTS: The estimation of fat-free mass was higher using BCM than DEXA, with a mean difference of -2.8 kg and limits of agreement (mean ± 2 SD) ranging from -12 kg to 6.5 kg. The estimation of fat mass was lower using BCM than DEXA, with a mean difference of 3.1 kg and limits of agreement (mean ± 2 SD) ranging from -6.8 kg to 13 kg. The measurement differences were significantly related to lean tissue index, fat tissue index, extracellular water, intracellular water, extracellular water/intracellular water, total body water, and overhydration. CONCLUSION: Our study showed a limited agreement between DEXA and bioimpedance, indicating that these 2 measurements are not interchangeable in nondialysis patients with chronic kidney disease. Lean tissue index, fat tissue index, and body water might contribute to the measurement differences, while measured glomerular filtration rate is not a factor associated with the measurement differences for body composition. Thus, we suggest that the same measure of body composition be used over time.

Sarcopenia and relationships between muscle mass, measured glomerular filtration rate and physical function in patients with chronic kidney disease stages 3-5.

Background: Sarcopenia and poor physical function are common in patients with chronic kidney disease (CKD). Our aim was to investigate the relationships between muscle mass and measured glomerular filtration rate (GFR) and between muscle mass and strength and balance, respectively, in patients with CKD stages 3-5. Methods: This is a baseline data analysis of a randomized controlled clinical trial. A total of 148 adult patients with an estimated GFR <30 mL/min/1.72 m2, not on renal replacement therapy, irrespective of the number of comorbidities were included from the Department of Nephrology, Skåne University Hospital, Lund, from 2011 to 2016. Body composition was measured by dual-energy X-ray absorptiometry (DEXA). GFR was measured by iohexol clearance. Balance was measured by functional reach and the Berg balance test and strength by handgrip strength and isometric quadriceps strength. Results: Measured GFR ranged from 8 to 55 mL/min/1.73 m2. Lean mass (P < 0.05), fat mass (P < 0.05), appendicular skeletal muscle (P < 0.001) and appendicular skeletal muscle index (P < 0.05) were associated with GFR. Functional reach was associated with leg lean mass (P < 0.05) and the Berg balance test score was associated with trunk lean mass (P < 0.05). Handgrip strength was associated with arm lean mass (P < 0.001). Isometric quadriceps strength was associated with leg lean mass (P < 0.001). More men (44%) suffered from low muscle mass than women (22%), whereas more women (36%) suffered from low muscle strength than men (26%). However, when combining both, men (16%) suffered from sarcopenia to a greater extent than women (8%). Conclusions: Among patients with CKD stages 3-5, loss of lean body mass, especially appendicular skeletal muscle, was significantly related to GFR decline. Two important markers of physical function, balance and strength, were significantly related to muscle mass. Moreover, men were more prone to sarcopenia than women during kidney function decline.

Relationships between abdominal aortic calcification, glomerular filtration rate, and cardiovascular risk factors in patients with non-dialysis dependent chronic kidney disease
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BACKGROUND: Abdominal aortic calcification (AAC) is an established risk factor for cardiovascular events in patients with chronic kidney disease (CKD). We hypothesized that AAC is associated with a decline in glomerular filtration rate (GFR) as well as with some other cardiovascular risk factors. MATERIALS AND METHODS: This is a cross-sectional analysis of baseline data from a randomized controlled clinical trial (RENEXC). A total of 151 patients (aged 66 ± 14 years) with an average measured GFR (mGFR) of 22.5 ± 8.2 mL/min/1.73m2, not on renal replacement therapy, irrespective of number of comorbidities, were included. GFR was measured with iohexol clearance and estimated using cystatin C- and creatinine-based equations (eGFR). AAC was evaluated with lateral lumbar X-ray using the scoring system described by Kauppila. All patients underwent laboratory analyses, 24-hour ambulatory blood pressure monitoring, and standard echocardiography. Multiple linear regression analyses controlling for sex, age, cardiovascular comorbidities, and hypertension were performed. RESULTS: The prevalence of AAC in this group of patients was 73%, and 47% had severe calcification (AAC score ≥ 7). More men (76%) had AAC than women (69%). AAC score was associated with mGFR (p = 0.03), eGFR (p = 0.006), plasma albumin (p = 0.006), plasma phosphate (p = 0.01), pulse pressure (p = 0.004), left ventricular mass (LVM) (p = 0.02), left atrial volume (LAV; p < 0.001), and left atrial volume index (LAVI; p = 0.001). CONCLUSION: AAC was highly prevalent in CKD. The degree of calcification in the abdominal aorta was strongly associated with a decline in GFR, a decrease in plasma albumin, an increase in plasma phosphate, an increase in pulse pressure, and cardiac structural changes, such as an increase in LVM, LAV, and LAVI.
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Using Next-Generation Sequencing to Identify a Mutation in Human MCSU that is Responsible for Type II Xanthinuria.

BACKGROUND: Hypouricemia is caused by various diseases and disorders, such as hepatic failure, Fanconi renotubular syndrome, nutritional deficiencies and genetic defects. Genetic defects of the molybdoflavoprotein enzymes induce hypouricemia and xanthinuria. Here, we identified a patient whose plasma and urine uric acid levels were both extremely low and aimed to identify the pathogenic gene and verify its mechanism. METHODS: Using next-generation sequencing (NGS), we detected a mutation in the human molybdenum cofactor sulfurase (MCSU) gene that may cause hypouricemia. We cultured L02 cells, knocked down MCSU with RNAi, and then detected the uric acid and MCSU concentrations, xanthine oxidase (XOD) and xanthine dehydrogenase (XDH) activity levels, and xanthine/hypoxanthine concentrations in cell lysates and culture supernatants. RESULTS: The NGS results showed that the patient had a mutation in the human MCSU gene. The in vitro study showed that RNAi of MCSU caused the uric acid, human MCSU concentrations, the XOD and XDH activity levels among cellular proteins and culture supernatants to be extremely low relative to those of the control. However, the xanthine/hypoxanthine concentrations were much higher than those of the control. CONCLUSIONS: We strongly confirmed the pathogenicity of the human MCSU gene.

High concentrations of uric acid inhibit angiogenesis via regulation of the Krüppel-like factor 2-vascular endothelial growth factor-A axis by miR-92a.

BACKGROUND: Angiogenesis is a critical component of many pathological conditions, and microRNAs (miRNAs) are indispensable in angiogenesis. It is unclear whether miRNAs regulate angiogenesis in the presence of high concentrations of uric acid (HUA), and the underlying mechanisms remain unknown. METHODS AND RESULTS: It was found that HUA inhibited the angiogenic ability of endothelial cells. miRNA expression profiling was conducted using microarray assays in HUA-stimulated endothelial cells. Eighteen differentially expressed miRNAs were subjected to bioinformatic analyses. The results indicated that miR-92a was negatively regulated and was closely related to angiogenesis. Furthermore, the effects of miR-92a on HUA-stimulated endothelial cell angiogenesis and the underlying mechanisms were investigated in dual-luciferase reporter assays, electrophoretic mobility shift assays, immunoblot assays, and tube formation assays. It was determined that Krüppel-like factor 2 (KLF2) is a target gene of miR-92a, and KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. miR-92a and VEGFA overexpression or KLF2 downregulation alleviates the HUA-mediated inhibition of angiogenesis in endothelial cells in vitro. CONCLUSIONS: This study reported that there is a novel pathway regulating angiogenesis under HUA conditions. In the presence of HUA, miR-92a downregulation increased KLF2 expression, subsequently inhibiting VEGFA, which resulted in decreased angiogenesis. Thus, this study reports a possible mechanism for cardiovascular injury caused by hyperuricemia and suggests that the miR-92a-KLF2-VEGFA axis may be a target for hyperuricemia treatment.

Bone mineral density after exercise training in patients with chronic kidney disease stages 3 to 5: a sub-study of RENEXC-a randomized controlled trial.

Background: We evaluated the effects of 12 months of exercise training on bone mineral density (BMD) in patients with chronic kidney disease (CKD) stages 3-5 not on kidney replacement therapy (KRT). Methods: A total of 151 patients were randomized to 12 months of either balance or strength training, both together with endurance training. Some 112 patients completed and 107 (69 men, 38 women) were analysed, with a mean age 66 ± 13.5 years and 31% having diabetes. The exercise training was self-administered, prescribed and monitored by a physiotherapist. Total body, hip and lumbar BMD, T score and Z score were measured at baseline and after 12 months using dual energy X-ray absorptiometry. Results: Both groups showed increased physical performance. The prevalence of osteoporosis and osteopenia was unchanged. The strength group (SG) decreased total body BMD (P < .001), the balance group (BG) increased total body T score (P < .05) and total body Z score (P < .005). Total body ΔT score was negative in the SG and unchanged in the BG (P < .005). Total body ΔZ score was negative in the SG and positive in the BG (P < .001). The proportion of progressors measured by ΔT (P < .05) and ΔZ scores (P < .05) was significantly lower in the BG compared with the SG. In multivariate logistic regression analysis, belonging to the BG was the only factor with a lower risk of deterioration of total body BMD, T and Z scores. Conclusions: Twelve months of balance training together with endurance training seemed to be superior to strength training in maintaining and improving BMD in patients with CKD not on KRT.

Long noncoding RNA MALAT-1: A versatile regulator in cancer progression, metastasis, immunity, and therapeutic resistance.

Long noncoding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides that do not code for proteins but have been linked to cancer development and metastasis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) influences crucial cancer hallmarks through intricate molecular mechanisms, including proliferation, invasion, angiogenesis, apoptosis, and the epithelial-mesenchymal transition (EMT). The current article highlights the involvement of MALAT-1 in drug resistance, making it a potential target to overcome chemotherapy refractoriness. It discusses the impact of MALAT-1 on immunomodulatory molecules, such as major histocompatibility complex (MHC) proteins and PD-L1, leading to immune evasion and hindering anti-tumor immune responses. MALAT-1 also plays a significant role in cancer immunology by regulating diverse immune cell populations. In summary, MALAT-1 is a versatile cancer regulator, influencing tumorigenesis, chemoresistance, and immunotherapy responses. Understanding its precise molecular mechanisms is crucial for developing targeted therapies, and therapeutic strategies targeting MALAT-1 show promise for improving cancer treatment outcomes. However, further research is needed to fully uncover the role of MALAT-1 in cancer biology and translate these findings into clinical applications.

Designing lithium halide solid electrolytes.

All-solid-state lithium batteries have attracted widespread attention for next-generation energy storage, potentially providing enhanced safety and cycling stability. The performance of such batteries relies on solid electrolyte materials; hence many structures/phases are being investigated with increasing compositional complexity. Among the various solid electrolytes, lithium halides show promising ionic conductivity and cathode compatibility, however, there are no effective guidelines when moving toward complex compositions that go beyond ab-initio modeling. Here, we show that ionic potential, the ratio of charge number and ion radius, can effectively capture the key interactions within halide materials, making it possible to guide the design of the representative crystal structures. This is demonstrated by the preparation of a family of complex layered halides that combine an enhanced conductivity with a favorable isometric morphology, induced by the high configurational entropy. This work provides insights into the characteristics of complex halide phases and presents a methodology for designing solid materials.

Identification of Hub Genes and Potential Molecular Pathogenesis in Substantia Nigra in Parkinson's Disease via Bioinformatics Analysis.

Parkinson's disease (PD) is the second most common neurodegenerative disease, with significant socioeconomic burdens. One of the crucial pathological features of PD is the loss of dopaminergic neurons in the substantia nigra (SN). However, the exact pathogenesis remains unknown. Moreover, therapies to prevent neurodegenerative progress are still being explored. We performed bioinformatics analysis to identify candidate genes and molecular pathogenesis in the SN of patients with PD. We analyzed the expression profiles, GSE49036 and GSE7621, which included 31 SN tissues in PD samples and 17 SN tissues in healthy control samples, and identified 86 common differentially expressed genes (DEGs). Then, GO and KEGG pathway analyses of the identified DEGs were performed to understand the biological processes and significant pathways of PD. Subsequently, a protein-protein interaction network was established, with 15 hub genes and four key modules which were screened in this network. The expression profiles, GSE8397 and GSE42966, were used to verify these hub genes. We demonstrated a decrease in the expression levels of 14 hub genes in the SN tissues of PD samples. Our results indicated that, among the 14 hub genes, DRD2, SLC18A2, and SLC6A3 may participate in the pathogenesis of PD by influencing the function of the dopaminergic synapse. CACNA1E, KCNJ6, and KCNB1 may affect the function of the dopaminergic synapse by regulating ion transmembrane transport. Moreover, we identified eight microRNAs (miRNAs) that can regulate the hub genes and 339 transcription factors (TFs) targeting these hub genes and miRNAs. Subsequently, we established an mTF-miRNA-gene-gTF regulatory network. Together, the identification of DEGs, hub genes, miRNAs, and TFs could provide better insights into the pathogenesis of PD and contribute to the diagnosis and therapies.

Construction of a flower-like SnS2/SnO2 junction for efficient photocatalytic CO2 reduction.

Photoreduction of CO2 to value-added chemicals and fuels is an attractive solution to alleviate environmental problems and energy crisis at the same time. However, engineering efficient photocatalysts with high activity and product selectivity is still challenging. Herein, we achieved three-dimensional (3D) spatial configuration design at micro-scale and heterogeneous interface construction at nano-scale on a SnS2/SnO2 composite, which featured hierarchical flower-like morphology consisted of nanosheets and type-II semiconductor structure. It behaved excellent selectivity and impressive photocatalytic CO2-to-CO performance with a yielding rate of 60.85 µmol g-1h-1, roughly 3 times higher than that of SnS2 and was in the front rank of this kind catalysts under 300 W Xe lamp illumination without using any sensitizers or noble metals. The enhanced catalytic capability could be attributed to the elaborately built structure with suitable energetic position that afforded effective separation and migration of photo-generated electron/hole pairs as well as enhanced light caption and absorption. Meanwhile, main reactive intermediates (e.g., CO2- and *COOH) were captured by in-situ Fourier transform infrared spectroscopy (FTIR), suggesting a fluent catalytic pathway on the SnS2/SnO2 platform. This work provides a new scheme to build advanced catalysts based on multiscale design and rational phase assembling.

Anti-Apoptosis Therapy for Meniscal Avascular Zone Repair: A Proof-of-Concept Study in a Lapine Model.

In the present study, 24 rabbits were firstly used to evaluate the apoptosis index and matrix degeneration after untreated adult meniscal tears. Vertical tears (0.25 cm in length) were prepared in the avascular zone of the anterior horn. Specimens were harvested at 1, 3, 6, 12 weeks postoperatively. The apoptosis index around tear sites stayed at a high level throughout the whole follow-up period. The depletion of glycosaminoglycans (GAG) and aggrecan at the tear site was observed, while the deposition of COL I and COL II was not affected, even at the last follow-up of 12 weeks after operation. The expression of SOX9 decreased significantly; no cellularity was observed at the wound interface at all timepoints. Secondly, another 20 rabbits were included to evaluate the effects of anti-apoptosis therapy on rescuing meniscal cells and enhancing meniscus repair. Longitudinal vertical tears (0.5 cm in length) were made in the meniscal avascular body. Tears were repaired by the inside-out suture technique, or repaired with sutures in addition to fibrin gel and blank silica nanoparticles, or silica nanoparticles encapsulating apoptosis inhibitors (z-vad-fmk). Samples were harvested at 12 months postoperatively. We found the locally administered z-vad-fmk agent at the wound interface significantly alleviated meniscal cell apoptosis and matrix degradation, and enhanced meniscal repair in the avascular zone at 12 months after operation. Thus, local administration of caspase inhibitors (z-vad-fmk) is a promising therapeutic strategy for alleviating meniscal cell loss and enhancing meniscal repair after adult meniscal tears in the avascular zone.

Solid Polymer Electrolytes with High Conductivity and Transference Number of Li Ions for Li-Based Rechargeable Batteries.

Smart electronics and wearable devices require batteries with increased energy density, enhanced safety, and improved mechanical flexibility. However, current state-of-the-art Li-based rechargeable batteries (LBRBs) use highly reactive and flowable liquid electrolytes, severely limiting their ability to meet the above requirements. Therefore, solid polymer electrolytes (SPEs) are introduced to tackle the issues of liquid electrolytes. Nevertheless, due to their low Li+ conductivity and Li+ transference number (LITN) (around 10-5 S cm-1 and 0.5, respectively), SPE-based room temperature LBRBs are still in their early stages of development. This paper reviews the principles of Li+ conduction inside SPEs and the corresponding strategies to improve the Li+ conductivity and LITN of SPEs. Some representative applications of SPEs in high-energy density, safe, and flexible LBRBs are then introduced and prospected.

Activation of Sonic hedgehog signaling pathway in S-type neuroblastoma cell lines.

The effects of Sonic hedgehog (Shh) signaling pathway activation on S-type neuroblastoma (NB) cell lines and its role in NB tumorigenesis were investigated. Immunohistochemistry was used to detect the expression of Shh pathway components-Patched1 (PTCH1) and Gli1 in 40 human primary NB samples. Western blotting and RT-PCR were used to examine the protein expression and mRNA levels of PTCH1 and Gli1 in three kinds of S-type NB cell lines (SK-N-AS, SK-N-SH and SHEP1), respectively. Exogenous Shh was administrated to activate Shh signaling pathway while cyclopamine was used as a selective antagonist of Shh pathway. S-type NB cell lines were treated with different concentrations of Shh or/and cyclopamine for different durations. Cell viability was measured by using MTT method. Apoptosis rate and cell cycle were assayed by flow cytometry. The xenograft experiments were used to evaluate the role of Shh pathway in tumor growth in immunodeficient mice. High-level expression of PTCH1 and Gli1 was detected in both NB samples and S-type NB cell lines. Cyclopamine decreased the survival rate of the three cell lines while Shh increased it, and the inhibition effects of cyclopamine could be partially reversed by shh pre-treatment. Cyclopamine induced the cell apoptosis and the cell cycle arrest in G0/G1 phase, while Shh induced the reverse effects and could partially prevent effects of cyclopamine. Cyclopamine could also inhibit the growth of NB in vivo. Our studies revealed that activation of the Shh pathway is important for survival and proliferation of S-type NB cells in vivo and in vitro through affecting cell apoptosis and cell cycle, suggesting a new therapeutic approach to NB.

Regulating the Grain Orientation and Surface Structure of Primary Particles through Tungsten Modification to Comprehensively Enhance the Performance of Nickel-Rich Cathode Materials.

Nickel-rich layered oxides, as the most promising commercial cathode material for high-energy density lithium-ion batteries, experience significant surface structural instabilities that lead to severe capacity deterioration and poor thermal stability. To address these issues, radially aligned grains and surface LixNiyWzO-like heterostructures are designed and obtained with a simple tungsten modification strategy in the LiNi0.91Co0.045Mn0.045O2 cathode. The formation of radially aligned grains, manipulated by the WO3 modifier during synthesis, provides a fast Li+ diffusion channel during the charge/discharge process. Moreover, the tungsten tends to enter into the lattice of the primary particle surface, and the armor-type tungsten-rich heterostructure protects the bulk material from microcracks, structural transformations, and surface side reactions. First-principles calculations indicate that oxygen is more stable in the surface tungsten-rich heterostructure than elsewhere, thus triggering an improved surface structural stability. Consequently, the 2 wt % WO3-modified LiNi0.91Co0.045Mn0.045O2 (NCM@2W) material shows outstanding prolonged cycling performance (capacity retention of 80.85% after 500 cycles) and excellent rate performance (5 C, 188.4 mA h g-1). In addition, its layered-to-rock salt phase transition temperature is increased by 80 °C compared with that of the pristine cathode. This work provides a novel surface modification approach and an in-depth understanding of the overall performance enhancement of nickel-rich layered cathodes.

A critical role of Sonic Hedgehog signaling in maintaining the tumorigenicity of neuroblastoma cells.

Accumulated evidence suggests a major role for the activation of the Sonic Hedgehog (SHH) signaling pathway in the development of neural crest stem cells that give rise to the sympathetic nervous system. We therefore investigated the involvement of SHH signaling in the pathogenesis of neuroblastoma, a common childhood malignant tumor of the sympathetic nervous system. Human neuroblastoma cell lines and a majority of primary neuroblastoma specimens showed high-level expression of the pathway targets and components, indicating persistent activation of the SHH pathway. All of the neuroblastoma cell lines we examined expressed significant levels of SHH ligand, suggesting an autocrine, ligand-dependent activation of the SHH pathway in neuroblastoma cells. Inhibition of SHH signaling by cyclopamine induced apoptosis and blocked proliferation in all major types of neuroblastoma cells, and abrogated the tumorigenicity of neuroblastoma cells. Moreover, the knockdown of GLI2 in neuroblastoma BE (2)-C and SK-N-DZ cell lines resulted in the inhibition of colony formation. Our study has revealed a molecular mechanism for the persistent activation of the SHH pathway which promotes the development of neuroblastoma, and suggests a new approach for the treatment of this childhood malignant tumor. (Cancer Sci 2009; 100: 1848-1855).

Activation of sonic hedgehog signaling pathway in olfactory neuroblastoma.

OBJECTIVES: Sonic hedgehog (Shh) signaling pathway is associated with tumor development; however, the role of Shh signaling in the development of olfactory neuroblastoma (ONB) is unknown. This study aimed to investigate the relationship between the regulation of Shh signaling and the pathogenesis of ONB. METHODS: The expression of Shh signaling components was characterized by immunohistochemistry in human non-tumor olfactory epithelium and ONB specimens, and by RT-PCR and immunoblotting in human ONB cell lines. The impact of the treatment with cyclopamine (a selective inhibitor of the Shh pathway) and/or exogenous Shh on ONB cell proliferation, cycle and apoptosis was examined by MTT, soft agar colony formation and flow cytometry assays, respectively. The influence of Shh signaling on the expression of Shh signaling components and cell cycle-related regulators was determined by immunoblotting and quantitative RT-PCR, respectively. RESULTS: The expression of Pacthed1, Gli1 and Gli2 was detected in 70, 70, and 65% of human ONB specimens, respectively, and in proportion of ONB cell lines, but not in non-tumor olfactory epithelium. Treatment with cyclopamine inhibited the proliferation and colony formation of ONB cells, induced ONB cell cycle arrest and apoptosis, and down-regulated the expression of Pacthed1, Gli1 and cyclin D1, but up-regulated p21 expression in vitro. These regulatory effects of cyclopamine were partially or completely erased by exogenous Shh. CONCLUSION: These data suggest that the Shh signaling pathway is crucial for the growth of ONB.