Green Synthesis of MOF-Mediated pH-Sensitive Nanomaterial AgNPs@ZIF-8 and Its Application in Improving the Antibacterial Performance of AgNPs.

Purpose: Herein, an emerging drug delivery system was constructed based on zeolite imidazole backbone (ZIF-8) to improve antibacterial defects of nanosilver (AgNPs), such as easily precipitated and highly cytotoxic. Methods: The homogeneous dispersion of AgNPs on ZIF-8 was confirmed by UV-Vis spectroscopy, FTIR spectroscopy, particle size analysis, zeta potential analysis, and SEM. The appropriate AgNPs loading ratio on ZIF-8 was screened through the cell and antibacterial experiments based on biosafety and antibacterial performance. The optimal environment for AgNPs@ZIF-8 to exert antibacterial performance was probed in the context of bacterial communities under different acid-base conditions. The potential mechanism of AgNPs@ZIF-8 to inhibit the common clinical strains was investigated by observing the biofilm metabolic activity and the level of reactive oxygen species (ROS) in bacteria. Results: The successful piggybacking of AgNPs by ZIF-8 was confirmed using UV-Vis spectroscopy, FTIR spectroscopy, particle size analysis, zeta potential analysis, and SEM characterization methods. Based on the bacterial growth curve (0-24 hours), the antibacterial ability of AgNPs@ZIF-8 was found to be superior to AgNPs. When the mass ratio of ZIF-8 and AgNPs was 1:0.25, the selection of AgNPs@ZIF-8 was based on its superior antimicrobial efficacy and enhanced biocompatibility. Notably, under weakly acidic bacterial microenvironments (pH=6.4), AgNPs@ZIF-8 demonstrated a more satisfactory antibacterial effect. In addition, experiments on biofilms showed that concentrations of AgNPs@ZIF-8 exceeding 1×MIC resulted in more than 50% biofilm removal. The nanomedicine was found to increase ROS levels upon detecting the ROS concentration in bacteria. Conclusion: Novel nanocomposites consisting of low cytotoxicity drug carrier ZIF-8 loaded with AgNPs exhibited enhanced antimicrobial effects compared to AgNPs alone. The pH-responsive nano drug delivery system, AgNPs@ZIF-8, exhibited superior antimicrobial activity in a mildly acidic environment. Moreover, AgNPs@ZIF-8 effectively eradicated pathogenic bacterial biofilms and elevated the intracellular level of ROS.

PM2.5 exposure and its interaction of oxidative balance score on ovarian cancer survival: A prospective cohort study.

Recent evidence advises particles with a diameter of 2.5 µm or less (PM2.5) might be a prognostic factor for ovarian cancer (OC) survival. The oxidative balance score (OBS) incorporates diet-lifestyle factors to estimate individuals' anti-oxidant exposure status which may be relevant to cancer prognosis. We aimed to investigate the roles of PM2.5, and OBS and their interaction in OC prognosis. 663 patients with OC were enrolled in the current study. Satellite-derived annual average exposures to PM2.5 based on patients' residential locations. The OBS was calculated based on 16 different diet-lifestyle components derived using an acknowledged self-reported questionnaire. The Cox regression model was performed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS). We also assessed the effect of modification between PM2.5 and OS by OBS via interaction terms. During a median follow-up of 37.57 (interquartile:35.27-40.17) months, 123 patients died. Compared to low-concentration PM2.5 exposure, high PM2.5 during 1 year before diagnosis was associated with worse OC survival (HR= 1.19, 95% CI = 1.01-1.42). We observed an improved OS with the highest compared with the lowest OBS (HR = 0.46, 95% CI = 0.27-0.79, P for trend < 0.05). Notably, we also found an additive interaction between low OBS and high exposure to PM2.5, with the corresponding associations of PM2.5 being more pronounced among participants with lower OBS (HR = 1.42, 95% CI = 1.09-1.86). PM2.5 may blunt OC survival, but high OBS represented an antioxidative performance that could alleviate the adverse association of PM2.5 and OS.

The association of macronutrient quality and its interactions with energy intake with survival among patients with ovarian cancer: results from a prospective cohort study.

BACKGROUND: Emerging evidence supports shifting the focus from the quantity of macronutrients to quality to obtain greater benefits for the prognosis of ovarian cancer (OC). Additionally, despite the high relevance between macronutrient quality and quantity, the interaction of these parameters on OC survival remains unknown. OBJECTIVE: A multidimensional macronutrient quality index (MQI) was applied to investigate the association between overall macronutrient quality and the survival of patients with OC. METHODS: A prospective cohort study was conducted with 701 females diagnosed with OC who were enrolled from 2015 to 2020. Dietary intake information was obtained from a validated food frequency questionnaire. The MQI was calculated based on 3 quality indices: carbohydrate quality index (CQI), fat quality index (FQI), and protein quality index (PQI). Cox proportional hazards regression was conducted to calculate HRs and 95% CIs. Furthermore, we evaluated whether energy intake status (total energy intake and energy balance) modified the association between MQI and OC survival. RESULTS: During a median follow-up period of 38 (interquartile: 35-40) mo, 130 deaths occurred. The prediagnosis high MQI scores were associated with substantially improved survival among females with OC (HRtertile 3 vs. tertile 1 = 0.50, 95% CI: 0.33, 0.77). For sub-indices of the MQI, higher CQI (HR = 0.60, 95% CI: 0.36, 0.99), higher FQI (HR = 0.55, 95% CI: 0.34, 0.87), and higher PQI (HR = 0.58, 95% CI: 0.35, 0.94) scores were all associated with better survival. Notably, significant interactions were observed for the MQI score with total energy intake and energy balance as well as the quantity and quality of carbohydrates on survival. CONCLUSIONS: Intake of high-quality macronutrients before diagnosis was associated with improved survival among females with OC, especially for those with energy imbalance.

Nutrients-Rich Food Index Scores and the Overall Survival of Ovarian Cancer Patients: Results from the Ovarian Cancer Follow-Up Study, a Prospective Cohort Study.

Background: The nutrients-rich food (NRF) index provides a score of diet quality. Although high diet quality is associated with survival of ovarian cancer (OC), the associations between NRF index scores and OC survival remain unevaluated. Methods: The prospective cohort study enrolled 703 women with newly diagnosed epithelial OC to assess the correlations between NRF index scores and overall survival (OS) in OC patients. Dietary consumption was evaluated through a food frequency questionnaire and diet quality was calculated based on NRF index scores, including three limited nutrients and six (NRF6.3), nine (NRF9.3), or eleven (NRF11.3) benefit nutrients. All-cause deaths were ascertained through medical records combined with active follow-up. Immunohistochemistry (IHC) analyses were conducted to evaluate the expression of IHC indicators (including Estrogen Receptor, Progesterone Receptor, p53, Vimentin, and Wilms' tumor 1), which were identified by two independent pathologists. The Cox proportional hazards regression models were applied for estimating the hazard ratios (HRs) and 95% confidence intervals (CIs). Moreover, we performed the penalized cubic splines model to assess the curvilinear associations of NRF index scores with OC survival. Results: During the median follow-up of 37.17 (interquartile: 24.73-50.17) months, 130 deaths were documented. Compared to the lowest tertiles, the highest tertile of index scores [NRF9.3 (HR = 0.63, 95% CI = 0.41-0.95), NRF6.3 (HR = 0.59, 95% CI = 0.39-0.89), and NRF11.3 (HR = 0.57, 95% CI = 0.38-0.87)] were correlated to better OS, showing an obvious linear trend (all p trend < 0.05). Interestingly, the curvilinear association between the NRF6.3 index score and OC survival was also observed (p non-linear < 0.05). Subgroup analyses, stratified by clinical, demographic, and IHC features, showed similar risk associations as the unstratified results. Furthermore, there were significant multiplicative interactions between NRF index scores and Progestogen Receptors as well as Wilms' tumor 1 expressions (all p interaction < 0.05). Conclusions: Higher NRF index scores were associated with an improved OS in OC patients.

Association between pre-diagnostic dietary antioxidant vitamin consumption and ovarian cancer survival: a prospective cohort study.

Background: Epidemiological evidence regarding the relationship between dietary antioxidant vitamin intake and ovarian cancer (OC) survival is not clear. Herein, we aimed to first evaluate this topic in a prospective cohort study in China. Methods: The present study included participants from the Ovarian Cancer Follow-Up Study, which was a hospital-based prospective cohort study including OC patients who were aged 18 to 79 years during 2015-2020. The information on the intake of antioxidant vitamins, consisting of vitamin A, retinol, α-carotene, ß-carotene, vitamin C, and vitamin E, and other diet information was obtained through a 111-item food frequency questionnaire. Deaths were recorded until March 31, 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival were evaluated using Cox proportional hazards models. Results: There were 130 (18.49%) deaths among 703 OC patients during a median 37.19 months follow-up. In the multivariable-adjusted model, the highest tertile of dietary vitamin C (HR = 0.43, 95% CI = 0.25-0.75, P for trend <0.05) and ß-carotene intake (HR = 0.52, 95% CI = 0.31-0.87, P for trend <0.05) was inversely associated with the overall survival of OC when compared with the lowest tertile group. Retinol, vitamin A, vitamin E, and α-carotene consumption showed no association with OC survival. Of note is that the multiplicative interaction was identified between vitamin C intake and residual lesions in OC survival (P for interaction <0.05). Conclusion: Our findings indicate that pre-diagnostic higher vitamin C and ß-carotene intake was associated with improved OC survival.

The oral bioaccessibility and gingival cytotoxicity of metal(loid)s in wild vegetables from mining areas: Implication for human oral health.

Background: Heavy metal(loid)s are frequently detected in vegetables posing potential human health risks, especially for those grown around mining areas. However, the oral bioaccessibility and gingival cytotoxicity of heavy metals in wild vegetables remain unclear. Methods: In this study, we assessed the total and bioaccessible Cr, As, Cd, Pb, and Ni in four wild vegetables from mining areas in Southwest China. In addition, the cytotoxicity and underlying mechanisms of vegetable saliva extracts on human gingival epithelial cells (HGEC) were studied. Results: The Plantago asiatica L. (PAL) showed the highest bioaccessible Cr, As, Cd, and Pb, while the greatest bioaccessible Ni was in Taraxacum mongolicum (TMM). The Pteridium aquilinum (PAM), Chenopodium album L. (CAL), and TMM extracts decreased cell viability, induced apoptosis, caused DNA damage, and disrupted associated gene expressions. However, PAL extracts which have the highest bioaccessible heavy metals did not present adverse effects on HGEC, which may be due to its inhibition of apoptosis by upregulating p53 and Bcl-2. Conclusion: Our results indicated that polluted vegetable intake caused toxic effects on human gingiva. The heavy metals in vegetables were not positively related to human health risks. Collectively, both bioaccessibility and toxic data should be considered for accurate risk assessment.

Single NV centers array preparation and static magnetic field detection.

To solve the problem of static magnetic field detection accuracy and consistency, we prepared an array of single NV centers for static magnetic field vector and gradient detection using the femtosecond laser direct writing method. The prepared single NV centers are characterized by fewer impurity defects and good stress uniformity, with an average spatial positioning error of only 0.2 µm. This array of single NV centers can achieve high accuracy magnetic field vector and gradient measurement with GBZ≈-0.047 µT/µm in the Z-axis. This result provides a new idea for large-range, high-precision magnetic field vector and gradient measurements.

Phytosterol intake and overall survival in newly diagnosed ovarian cancer patients: An ambispective cohort study.

Background: Phytosterol is a bioactive compound existing in all plant foods, which might have anticancer properties. The aim of this study was to first assess the impact of the pre-diagnosis phytosterol intake on overall survival (OS) of patients with ovarian cancer (OC). Materials and methods: This ambispective cohort study recruited 703 newly diagnosed OC patients to investigate the aforementioned associations. Dietary intake was assessed using a validated 111-item food frequency questionnaire. Deaths were ascertained until March 31, 2021, through active follow-up and medical records. Cox proportional hazards regression models were applied to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During the median follow-up of 37.17 months, 130 deaths occurred. The median age at diagnosis of 703 OC patients was 53.00 (interquartile: 48.00-60.00) years. Of these, almost half patients (48.08%) were diagnosed in advanced International Federation of Gynecology and Obstetrics (FIGO) stage (III-IV). Additionally, more than half patients were serous carcinoma (68.14%), poorly differentiated (85.21%), and no residual lesions (78.66%). Patients consumed the highest tertile of dietary campesterol (HR = 0.54, 95% CI = 0.31-0.94, P trend < 0.05), stigmasterol (HR = 0.60, 95% CI = 0.37-0.98), and ß-sitosterol (HR = 0.63, 95% CI = 0.40-0.99) were significantly associated with better OS compared with those with the lowest tertile of intake. The curvilinear associations were observed between total phytosterols and ß-sitosterol intake and OC survival (P non-linear < 0.05). Significant associations were generally consistent across different subgroups stratified by demographical, clinical, and immunohistochemical characteristics. Moreover, there were significant interactions between phytosterol intake and age at diagnosis, body mass index, as well as expressions of Wilms' tumor-1 and Progestogen Receptor (all P interaction < 0.05). Conclusion: Pre-diagnosis higher campesterol, stigmasterol, and ß-sitosterol intake were associated with better survival among OC patients.

Pre-diagnosis fiber : carbohydrate intake ratio and mortality of ovarian cancer: results from a prospective cohort study.

Background: The association between the ratio of fiber to carbohydrate (F : C-R) and cancer mortality is not currently well-known. We prospectively evaluated for the first time the aforementioned topic among ovarian cancer (OC) patients. Methods: A total of 703 newly diagnosed OC patients aged 18-79 years were included. Pre-diagnosis diet intake details were collected with a validated food frequency questionnaire. Deaths were ascertained until March 31, 2021, based on medical records and the cancer registry. Cox proportional hazard models were used to evaluate hazard ratios (HRs) and 95% confidence intervals (CIs) between pre-diagnostic fiber, carbohydrate, and F : C-R intake and OC mortality. Restricted cubic splines were used to analyze the potential nonlinear relationship between F : C-R and OC mortality. Results: During the follow-up period (median: 37.2 months; interquartile: 24.7-50.2 months), we observed 130 (18.49%) OC patients died. The pre-diagnosis higher fiber intake (comparing the highest with the lowest tertile of intake: HR = 0.56, 95% CI = 0.35-0.92; HR per 1 SD increment: 0.78, 95% CI = 0.64-0.96; P trend < 0.05) and higher F : C-R intake (comparing the highest with the lowest tertile of intake: HR = 0.51, 95% CI = 0.31-0.85; HR per 1-SD increment: 0.73; 95% CI = 0.59-0.91; P trend < 0.05) were significantly associated with lower mortality for OC patients, but no evidence of the association between pre-diagnosis carbohydrate intake and OC mortality was observed. We found no evidence of a nonlinear relationship between F : C-R and OC mortality. Significant inverse associations were also observed for subgroup analyses stratified by age at diagnosis, menopausal status, residual lesions, histological type, FIGO stage, and body mass index, although not all associations showed statistical significance. Conclusion: Pre-diagnosis high fiber intake and high F : C-R diet intake were associated with a decreased risk of OC mortality.

Phase customization in photonic integrated circuits with trimmed waveguides.

Accurate photon phase control on a chip is essential to improve the expandability and stability of photonic integrated circuits (PICs). Here, we propose a novel, to the best of our knowledge, on-chip static phase control method in which a modified line is added close to the normal waveguide with a lower-energy laser. By controlling the laser energy and the position and length of the modified line, the optical phase can be precisely controlled with low loss and a three-dimensional (3D) path. Customizable phase modulation ranging from 0 to 2π is performed with a precision of λ/70 in a Mach-Zehnder interferometer. The proposed method can customize high-precision control phases without changing the waveguide's original spatial path, which is expected to control the phase and solve the phase error correction problem during processing of large-scale 3D-path PICs.

Evanescent Field Controllable MZ Sensor via Femtosecond Laser Processing and Mechanic Polishing.

Recently, optical sensors interacting with evanescent fields and the external environment around waveguides have attracted extensive attention. In the process of light propagation in the waveguide, the depth of the evanescent field is closely related to the accuracy of the optical sensor, and adjusting the depth of the evanescent field to obtain higher accuracy has become the primary challenge in fabricating on-chip optical sensors. In this study, the waveguide structure of a Mach-Zehnder interferometer was written directly in Corning Eagle 2000 borosilicate glass by a femtosecond laser, and the sensing window was exposed out of the bulk material by mechanical polishing. The refractive index detection device based on the proposed on-chip Mach-Zehnder interferometer has the advantages of small volume, light weight, and good stability. Its sensitivity can reach 206 nm/RIU or 337 dB/RIU, and the theoretical maximum measurement range is 1-1.508. Therefore, it can measure the refractive index quickly and accurately in extreme or complex environments, and has excellent application prospects.

Fabrication of spherical silica amino-functionalized microporous organic network composites for high performance liquid chromatography.

Microporous organic networks (MONs) are a potential class of microporous materials in analytical chemistry. As great efforts have been made in sample pretreatment and gas chromatography, the application of MONs in high performance liquid chromatography (HPLC) has largely lagged and has never been investigated. In addition, directly packing of MONs into columns for HPLC is impractical due to the high column pressure and low column efficiency resulted from the sub-micron sized and irregular MONs. To solve these issues and uncover the possibility of MONs in HPLC, here we report the fabrication of spherical silica amino-functionalized MON (SiO2@MON-NH2) composite as a novel stationary phase for HPLC. Neutral, acidic and alkaline probes were evaluated on SiO2@MON-NH2 packed column. A column efficiency of 21,246 plates per meter was obtained for n-propylbenzene. The results revealed the hydrophobic interaction was the main separation mechanism on SiO2@MON-NH2 packed column. Baseline separation of benzenediol, dichlorophenol, chlorophenol and phenylenediamine position isomers, deoxynucleosides and nucleosides was also achieved on SiO2@MON-NH2 packed column. The relative standard deviations of retention time, peak height and peak area for the studied position isomers, deoxynucleosides and nucleosides were 0.2-0.7%, 0.3-3.7% and 1.7-3.5%, respectively. The SiO2@MON-NH2 packed column also offered better resolution for dichlorophenol isomers, deoxynucleosides and nucleosides than SiO2-NH2 and commercial C18 columns. These results revealed the potential of MONs in HPLC and also provided a new way for the use of nano-sized or irregular MONs in HPLC.

Synthesis of silica amino-functionalized microporous organic network composites for efficient on-line solid phase extraction of trace phenols from water.

Microporous organic network (MON) is a promise class of functional materials in solid phase extraction (SPE). However, the previous MON-based SPE works are all focused on off-line mode. The inherent drawbacks of off-line SPE such as complicated operation steps and poor repeatability still hinder the potential applications of MON. In addition, direct use of traditional synthesized nano-sized MON in on-line SPE is impractical. To solve these issues, here we show the synthesis of silica amino-functionalized MON (SiO2@MON-NH2) microsphere as an advanced adsorbent for on-line SPE of trace phenols prior to the high performance liquid chromatography (HPLC) analysis. The SiO2 microsphere is served as the core to support the in-situ engineering of MON-NH2 to reduce the back pressure during on-line SPE. Integrating amino groups (hydrogen binding sites) with aromatic MON's networks (hydrophobic and π-π interaction sites) on SiO2@MON-NH2 provides supersensitive performance for phenols. The SiO2@MON-NH2 microsphere for on-line SPE coupled with HPLC for the analysis of five phenols offers low limit of detections (S/N = 3, 0.009-0.030 µg L-1), wide linear range (0.025-100 µg L-1), large enrichment factors (5036-5689) and good intra-day and inter-day precisions (RSDs, 0.7-1.6 and 1.0-2.7%, respectively). The proposed method is also successfully applied to analyze trace phenols in tap, lake and river water samples with good recoveries. The newly-synthesized MON composites own great potential in on-line SPE for further determination of diverse trace contaminants.

Synthesis of magnetic amino-functionalized microporous organic network composites for magnetic solid phase extraction of endocrine disrupting chemicals from water, beverage bottle and juice samples.

In this work, the magnetic amino-functionalized microporous organic network composites (Fe3O4@MON-NH2) were rational designed and facile synthesized for magnetic solid phase extraction (MSPE) of endocrine disrupting chemicals (EDCs), followed by their analysis with high-performance liquid chromatography. The incorporation of amino groups (hydrogen bonding sites) into hydrophobic MON-NH2 networks led to their good enrichment for four typical EDCs bisphenol A (BPA), 4-alpha-cumylphenol (4-α-CP), 4-tert-octylphenol (4-t-OP) and 4-nonylphenol (4-NP) relying on the pre-designed hydrogen bonding, π-π and hydrophobic interactions. The combination of MON-NH2 shell and magnetic Fe3O4 core provided a fast extraction of BPA, 4-α-CP, 4-t-OP and 4-NP from matrix solution. Under the optimal conditions, the developed method offered good linearity (R2 > 0.990) in the range of 0.05-1000 µg L-1, low limits of detection (S/N = 3) of 0.015-0.030 µg L-1 and large enrichment factors of 172-197 for the studied EDCs. The maximum adsorption capacities of BPA, 4-α-CP, 4-t-OP and 4-NP were 124.1, 105.6, 116.6 and 117.9 mg g-1, respectively. The Fe3O4@MON-NH2 gave larger selectivity for other polar phenols than non-polar polycyclic aromatic hydrocarbons, revealing the dominant role of hydrogen bonding interaction during the extraction and the potential of Fe3O4@MON-NH2 for other polar phenols. The developed method was successfully applied for the analysis of EDCs in water, orange juice and beverage bottle samples with the recoveries of 80.3-109.5%. These results revealed the potential of functional MONs as efficient adsorbents in sample pretreatment.

Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition.

To date, the molecular mechanism underlying constitutive signal transducer and activator of transcription 3 (STAT3) activation in gliomas is largely unclear. In this study, we report that Smad6 is overexpressed in nuclei of glioma cells, which correlates with poor patient survival and regulates STAT3 activity via negatively regulating the Protein Inhibitors of Activated STAT3 (PIAS3). Mechanically, Smad6 interacts directly with PIAS3, and this interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and the Ring domain of PIAS3. Smad6 recruits Smurf1 to facilitate PIAS3 ubiquitination and degradation, which also depends on the MH2 domain and the PY motif of Smad6. Consequently, Smad6 reduces PIAS3-mediated STAT3 inhibition and promotes glioma cell growth and stem-like cell initiation. Moreover, the Smad6 MH2 transducible protein restores PIAS3 expression and subsequently reduces gliomagenesis. Collectively, we conclude that nuclear-Smad6 enhances glioma development by inducing PIAS3 degradation and subsequent STAT3 activity upregulation.

Upregulation of microRNA-370 promotes cell apoptosis and inhibits proliferation by targeting PTEN in human gastric cancer.

Growing evidence suggests that microRNA plays an essential role in the development and metastasis of many tumors, including gastric cancer. Aberrant miR­370 expression has been indicated in tumor growth, but the mechanism of miR­370 inhibits both the proliferation and metastatic ability for gastric cancer remains unclear. Accumulating evidence reported that PTEN signaling pathway plays an important role in the cellular processes, such as apoptosis, cell growth and proliferation. The goal of this study was to identify whether miR­370 could inhibit the growth, migration, invasion, proliferation and metastasis of gastric cancer through targeting PTEN. Real-time PCR (RT-PCR) was used to quantify miR-370 expression in vitro experiments. The biological functions of miR­370 were determined via cell proliferation. Our study indicated that miR­370 targeted PTEN leading to activation of apoptosis signaling and the cell proliferation of cervical cancer cells, ameliorating gastric cancer growth and progression. In addition, the combination of miR­370 and PTEN inactivated AKT, MDM2 and mTOR while stimulated caspase-3, p53 and GSK3ß expression, promoting apoptosis and suppressing proliferation of gastric cancer cells. Therefore, our study revealed the mechanistic links between miR­370 and PTEN in the pathogenesis of gastric cancer through modulation of cell apoptosis and proliferation. Additionally, targeting miR­370 could serve as a novel strategy for future gastric cancer therapy clinically.

Curcumin induces G2/M arrest and triggers apoptosis via FoxO1 signaling in U87 human glioma cells.

It has previously been demonstrated that curcumin possesses an antitumor activity, which is associated with its ability to induce G2/M cell cycle arrest and apoptosis. However the detailed underlying mechanisms remain unclear. The present study aimed to investigate the efficacy and underlying mechanism of curcumin­induced cell cycle arrest and apoptosis in U87 human glioblastoma cells. By immunofluorescence staining, subcellular fractionation and western blotting, the present study demonstrated that curcumin was able to induce G2/M cell cycle arrest and apoptosis by increasing the expression levels of cyclin G2, cleaved caspase­3 and Fas ligand (FasL), and decreasing the expression of cyclin­dependent kinase 1 (CDK1). In addition, increased expression of forkhead box protein O1 (FoxO1) and decreased expression of phosphorylated (p)­FoxO1 were detected in the curcumin­treated U87 cells. Curcumin was also able to induce the translocation of FoxO1 from the cytoplasm to the nucleus. Furthermore, following knockdown of FoxO1 expression in curcumin­treated U87 cells using FoxO1 small interfering RNA, the expression levels of cyclin G2, cleaved caspase­3 and FasL were inhibited; however, the expression levels of CDK1 were not markedly altered. Notably, following knockdown of CDK1 expression under normal conditions, the total expression of FoxO1 was not affected; however, p­FoxO1 expression was decreased and FoxO1 nuclear expression was increased. Furthermore, curcumin­induced G2/M cell cycle arrest and apoptosis could be attenuated by FoxO1 knockdown. These results indicated that curcumin may induce G2/M cell cycle arrest and apoptosis in U87 cells by increasing FoxO1 expression. The present study identified a novel mechanism underlying the antitumor effects of curcumin, and may provide a theoretical basis for the application of curcumin in glioma treatment.

Combined Interactions of Plant Homeodomain and Chromodomain Regulate NuA4 Activity at DNA Double-Strand Breaks.

DNA double-strand breaks (DSBs) represent one of the most threatening lesions to the integrity of genomes. In yeast Saccharomyces cerevisiae, NuA4, a histone acetylation complex, is recruited to DSBs, wherein it acetylates histones H2A and H4, presumably relaxing the chromatin and allowing access to repair proteins. Two subunits of NuA4, Yng2 and Eaf3, can interact in vitro with methylated H3K4 and H3K36 via their plant homeodomain (PHD) and chromodomain. However, the roles of the two domains and how they interact in a combinatorial fashion are still poorly characterized. In this study, we generated mutations in the PHD and chromodomain that disrupt their interaction with methylated H3K4 and H3K36. We demonstrate that the combined mutations in both the PHD and chromodomain impair the NuA4 recruitment, reduce H4K12 acetylation at the DSB site, and confer sensitivity to bleomycin that induces DSBs. In addition, the double mutant cells are defective in DSB repair as judged by Southern blot and exhibit prolonged activation of phospho-S129 of H2A. Cells harboring the H3K4R, H3K4R, K36R, or set1Δ set2Δ mutant that disrupts H3K4 and H3K36 methylation also show very similar phenotypes to the PHD and chromodomain double mutant. Our results suggest that multivalent interactions between the PHD, chromodomain, and methylated H3K4 and H3K36 act in a combinatorial manner to recruit NuA4 and regulate the NuA4 activity at the DSB site.

[Relationship of iron overload to bone mass density and bone turnover in postmenopausal women with fragility fractures of the hip].

OBJECTIVE: To study relationships between serum ferritin and bone metabolism in patients with hip fragility fractures. METHODS: This cross-sectional study included 76 postmenopausal women with hip fracture from Feburary 2011 to June 2012. The mean age of the women was (73 ± 10) years (range, 55-93 years) and the mean duration of menstruation was (22 ± 10)years (range, 5-50 years). Serum concentrations of ferritin, transferrin, alkaline phosphatase (ALP), amino-terminal extension peptide of type I collagen (P1NP), C-terminal telopeptides of type I collagen (ß-CTX)and femoral and lumbar bone mineral density by dual-energy X-ray absorptiometry were measured. Bone metabolism was compared between normal and elevated ferritin groups with t-test, Pearson linear, partial correlation and multiple regression analysis examined associations between iron- and bone-related markers. RESULTS: Serum ferritin concentration raised to (230 ± 146)µg/L, transferrin concentration reduced to (1.89 ± 0.33)g/L. P1NP concentration raised to (61 ± 32) ng/L when the concentration of serum ALP and ß-CTX were in the normal range. T-scores for bone mineral density in the femoral neck (-2.0 ± 1.1) and lumbar (-2.1 ± 1.2) were below the normal ranges(-1.0-1.0). The subjects were divided into two groups according to serum ferritin concentration, normal group(serum ferritin concentration ≤ 150 µg/L, n = 25) and elevated group(serum ferritin concentration > 150 µg/L, n = 51). Patients of elevated group had lower bone mineral density in femoral neck and lumbar than normal group(t = 3.13,2.89, P < 0.01), and higher P1NP, ß-CTX concentration (t = -2.38, -3.59, P < 0.05) . In partial correlation analysis adjusted for confounders, serum ferritin concentration was correlated negatively with bone mineral density in both femoral neck and lumbar (r = -0.335,-0.295, P < 0.05), and positively with P1NP and ß-CTX (r = 0.467,0.414, P < 0.05), but not correlated with ALP (r = 0.188, P > 0.05). Transferrin concentration tended to be correlated positively with bone mineral density in both femoral neck and lumbar (r = 0.444, 0.262, P < 0.05) and negatively with ALP, P1NP and ß-CTX(r = -0.326,-0.285,-0.278, P < 0.05). CONCLUSIONS: Iron overload has a high prevalence in postmenopausal women with fragility fracture. Increased iron stores, which might lead to bone loss and lower bone mineral density by enhancing the activity of bone turnover, could be an independent factor to take effects on bone metabolism on postmenopausal women.

Relationship of iron overload to bone mass density and bone turnover in postmenopausal women with fragility fractures of the hip / 中华外科杂志

<p><b>OBJECTIVE</b>To study relationships between serum ferritin and bone metabolism in patients with hip fragility fractures.</p><p><b>METHODS</b>This cross-sectional study included 76 postmenopausal women with hip fracture from Feburary 2011 to June 2012. The mean age of the women was (73 ± 10) years (range, 55-93 years) and the mean duration of menstruation was (22 ± 10)years (range, 5-50 years). Serum concentrations of ferritin, transferrin, alkaline phosphatase (ALP), amino-terminal extension peptide of type I collagen (P1NP), C-terminal telopeptides of type I collagen (β-CTX)and femoral and lumbar bone mineral density by dual-energy X-ray absorptiometry were measured. Bone metabolism was compared between normal and elevated ferritin groups with t-test, Pearson linear, partial correlation and multiple regression analysis examined associations between iron- and bone-related markers.</p><p><b>RESULTS</b>Serum ferritin concentration raised to (230 ± 146)µg/L, transferrin concentration reduced to (1.89 ± 0.33)g/L. P1NP concentration raised to (61 ± 32) ng/L when the concentration of serum ALP and β-CTX were in the normal range. T-scores for bone mineral density in the femoral neck (-2.0 ± 1.1) and lumbar (-2.1 ± 1.2) were below the normal ranges(-1.0-1.0). The subjects were divided into two groups according to serum ferritin concentration, normal group(serum ferritin concentration ≤ 150 µg/L, n = 25) and elevated group(serum ferritin concentration > 150 µg/L, n = 51). Patients of elevated group had lower bone mineral density in femoral neck and lumbar than normal group(t = 3.13,2.89, P < 0.01), and higher P1NP, β-CTX concentration (t = -2.38, -3.59, P < 0.05) . In partial correlation analysis adjusted for confounders, serum ferritin concentration was correlated negatively with bone mineral density in both femoral neck and lumbar (r = -0.335,-0.295, P < 0.05), and positively with P1NP and β-CTX (r = 0.467,0.414, P < 0.05), but not correlated with ALP (r = 0.188, P > 0.05). Transferrin concentration tended to be correlated positively with bone mineral density in both femoral neck and lumbar (r = 0.444, 0.262, P < 0.05) and negatively with ALP, P1NP and β-CTX(r = -0.326,-0.285,-0.278, P < 0.05).</p><p><b>CONCLUSIONS</b>Iron overload has a high prevalence in postmenopausal women with fragility fracture. Increased iron stores, which might lead to bone loss and lower bone mineral density by enhancing the activity of bone turnover, could be an independent factor to take effects on bone metabolism on postmenopausal women.</p>