Association of immunohistochemical profiles with histotypes in endometrial carcinomas.

OBJECTIVE: Although a large number of endometrial cancer patients are cured with surgery alone, there are significant numbers of patients with more aggressive variants of endometrial carcinoma for whom the prognosis remains poor. We investigated the effects of prevalence, histotypes, and immunohistochemical profiles on prognostic value in a hospital-based population. MATERIALS AND METHODS: A retrospective study of surgically resected primary endometrial carcinoma was included. Immunohistochemical stains were performed on formalin-fixed paraffin-embedded tissue microarray sections for ß-Catenin, estrogen receptor (ER), progesterone receptor (PR), HER-2, MLH1, MSH2, MSH6, PMS2, and p53. RESULTS: Loss of mismatch repair expression was detected in 25.4% of samples (29/114, mean age 57 years) of the tumors. The following loss of expression was observed in patients: MLH1/PMS2 in 16.6% of patients, MSH6 in 7.0% of patients, MLH1 in 0.9% of patients, and MSH6/PMS2/MLH1 in 0.9% of patients. Immunohistochemistry of p53 was analyzed for 111 patients. A total of 13 patients (11.7%, mean age 64 years) had p53-abnormal expression (absent, cytoplasmic or diffuse strong positive patterns), and more than half (9/13, 69.2%) had endometrioid histotype. Abnormalities in p53 were significantly associated with histotype (p = 0.001), advanced tumor stage (p = 0.038), death of disease (p = 0.002), PR percentage (p = 0.002), and HER-2 expression (p = 0.018). Immunohistochemical nuclear localization of ß-Catenin was detected in 7.1% of the cohort. The combination of p53 and nuclear ß-Catenin expressions was not significantly predictive of disease-free or overall survival. CONCLUSION: The results of this study are useful for management of endometrial cancer in patients with DNA mismatch repair, abnormal p53 expression, or nuclear localization of ß-Catenin.

Development of a novel latent electrochemical molecular substrate for the real-time monitoring of the tumor marker aminopeptidase N in live cells, whole blood and urine.

Aminopeptidase N (APN/CD13) plays an important role in the growth and metastasis, of tumor, and is a potential biomarker for the post-treatment surveillance of cancer reoccurrence and progression of various malignancies. Thus, we have designed and prepared a convenient and ultrasensitive APN-targeting activity-based ratiometric electrochemical molecular substrate (Ala-AFC) for direct real-time monitoring of APN activity in biosamples. The APN in our experiment was used to hydrolyze the alanine moiety of the Ala-AFC probe and, as a result of this hydrolysis, realize concomitantly a cascade reaction to unmask the electrochemical reporter N-alkylated amino ferrocene (AAF). The Ala-AFC probe exhibited high sensitivity with a wide detection range of 0.05-110 ng mL-1 and a low limit of detection of 23.18 pg mL-1. The electrochemical signals were found to be distinctly specific for APN and free of interference from other electroactive biological species. Furthermore, the Ala-AFC probe was employed to monitor and quantify, in real-time, the activity of APN in tumor cells, whole blood, and urine. In addition, the results of our direct electrochemical quantifications of the amount of APN in whole blood and urine were found to be consistent with the results of the use of commercially available fluorometric assay kits to sense APN in serum and urine. Thus our approach shows promise as a point-of-care tool for cancer diagnostics and post-treatment surveillance of cancer reoccurrence.

Development of ratiometric electrochemical molecular switches to assay endogenous formaldehyde in live cells, whole blood and creatinine in saliva.

Formaldehyde is a reactive carbonyl species (RCS) that is produced naturally in the human body via metabolic and epigenetic biochemical processes, yet in high concentrations is highly toxic to the environment as well as to living organisms. Therefore, we designed two ratiometric electrochemical molecular redox probes, Formaldehyde oxidative latent probe (FOLP) and dihydroxy-formaldehyde oxidative latent probe (HFOLP), for the selective profiling of endogenous formaldehyde. FOLP and HFOLP each underwent the aza-Cope reaction with formaldehyde followed by hydrolysis to eliminate unmask redox reporter N-alkylated aminoferrocene (AAF) to monitor their response current. The FOLP and HFOLP sensors showed broad dynamic ranges of 0.12-1000 µM and 0.09-3 mM for formaldehyde with detection limits of 48.2 nM and 31.6 µM, respectively. Also, since formaldehyde is the byproduct of biochemical reactions for detecting creatinine and creatinine is an important biomarker for chronic kidney disease (CKD), we tested the FOLP probe for its ability to monitor creatinine. It successfully did so, and this ability was used to develop an electrochemical platform for the quantification of creatinine; it showed a dynamic range of 3.25-200 µM and a limit of detection (1.3 µM). In addition, the FOLP-based assay platform delivered a reliable analytical performance for the quantification of formaldehyde in human whole blood and of creatinine in saliva, and also for the real-time monitoring of endogenous formaldehyde secretion in HeLa cells. Moreover, the concentrations determined using our method were found to be consistent with those determined using formaldehyde and creatinine fluorometric assay kits.

The study of isotopic enrichment of water in human plasma and erythrocyte.

Life does not sustain without water. For water, there is a natural abundance of stable isotope hydrogen and oxygen. Water molecules get across cell membranes through a plasma membrane protein, named aquaporin. Moreover, the kidney is the main organ to maintain water homeostasis. Here, we study the stable isotopic ratios of hydrogen and oxygen in human blood plasma and erythrocyte corresponding to kidney functions. We extract waters from human plasma and erythrocyte, collected from 110 participants, including 51 clinically stable outpatients with end-stage renal disease (ESRD) and 59 subjects with normal renal function (NRF). We observed that (i) both extracellular (blood plasma) and intracellular (erythrocyte) biology waters are isotopic differences between the ESRD and NRF participants, (ii) the natural abundance of isotopic waters of ESRD is hypo-isotopic, and (iii) the isotopic enrichment of water between erythrocyte and blood plasma are distinct. In addition, we introduce an empirical formula using entropy transformation to describe isotopic water enrichment for biology. Accordingly, the natural abundance of stable isotope water of blood plasma and erythrocyte may be possibly put in practice a new sign for assessments of kidney dysfunctions.

Electrochemical substrate for active profiling of cellular surface leucine aminopeptidase activity and drug resistance in cancer cells.

Leucine aminopeptidase (LAP) is an essential proteolytic enzyme and potential biomarker for liver malignancy. Overexpression of LAP is directly linked with some fatal physiological and pathological disorders. In this regard, we have designed an activity based electrochemical substrate leucine-benzyl ferrocene carbamate (Leu-FC) for selective profiling of LAP activity in live cells. In practice, LAP instantaneously hydrolyze the Leu residue of the substrate Leu-FC to eliminate the unmasked electrochemical reporter amino ferrocene via predefined self-immolative cascade. The electrochemical signal is distinctly specific for LAP and free of other electroactive biological interference. The substrate Leu-FC empowered sensor displayed broad dynamic range with admirable detection limits. On top of this, the probe Leu-FC was employed in real-time active profiling of cellular LAP activity in HepG2 cells and effect of LAP inhibitor. In extent, the substrate Leu-FC can effectively monitor cisplatin induced overexpression of LAP activity in HepG2 cells in presence and absence of bestatin. The sensor showcased an excellent reliability towards monitoring cellular LAP activity in HepG2 cells. Unlike the traditional antibody-based immunoassays, our approach is capable of monitoring in-situ activity of LAP in live cells.

High amplitude bubble continuous positive airway pressure decreases lung injury in rats with ventilator-induced lung injury.

BACKGROUND: Bubble continuous positive airway pressure (BCPAP) has been used in neonates with respiratory distress for decades; however, the optimal setting for BCPAP circuits remains unknown. This study compared the gas exchange efficiency and lung protection efficacy between conventional and high-amplitude BCPAP devices. METHODS: We compared gas exchange, lung volume, and pulmonary inflammation severity among rats with ventilator-induced lung injury (VILI) that were treated with conventional BCPAP (BCPAP with an expiratory limb at 0°), high-amplitude BCPAP (BCPAP with an expiratory limb at 135°), or spontaneous breathing (SB). After mechanical ventilation for 90 minutes, the rats were randomly divided into four groups: a control group (euthanized immediately; n = 3), an SB group (n = 8), and two BCPAP groups that received BCPAP with the expiratory limb at either 0° (n = 8) or 135° (n = 7) for 90 minutes. RESULTS: The high-amplitude BCPAP group exhibited significantly lower alveolar protein, lung volume, and Interleukin-6 (IL-6) levels than did the SB group. The high-amplitude BCPAP group exhibited significantly lower IL-6 levels than did the conventional BCPAP group. The two BCPAP groups demonstrated no difference in gas exchange efficiency. CONCLUSION: High-amplitude BCPAP reduced lung inflammation and alveolar overdistension in rats with VILI after mechanical ventilation was ceased. Thus high-amplitude BCPAP may offer a superior lung protective effect than conventional BCPAP.

Sulfur Oxidation in the Acidophilic Autotrophic Acidithiobacillus spp.

Sulfur oxidation is an essential component of the earth's sulfur cycle. Acidithiobacillus spp. can oxidize various reduced inorganic sulfur compounds (RISCs) with high efficiency to obtain electrons for their autotrophic growth. Strains in this genus have been widely applied in bioleaching and biological desulfurization. Diverse sulfur-metabolic pathways and corresponding regulatory systems have been discovered in these acidophilic sulfur-oxidizing bacteria. The sulfur-metabolic enzymes in Acidithiobacillus spp. can be categorized as elemental sulfur oxidation enzymes (sulfur dioxygenase, sulfur oxygenase reductase, and Hdr-like complex), enzymes in thiosulfate oxidation pathways (tetrathionate intermediate thiosulfate oxidation (S4I) pathway, the sulfur oxidizing enzyme (Sox) system and thiosulfate dehydrogenase), sulfide oxidation enzymes (sulfide:quinone oxidoreductase) and sulfite oxidation pathways/enzymes. The two-component systems (TCSs) are the typical regulation elements for periplasmic thiosulfate metabolism in these autotrophic sulfur-oxidizing bacteria. Examples are RsrS/RsrR responsible for S4I pathway regulation and TspS/TspR for Sox system regulation. The proposal of sulfur metabolic and regulatory models provide new insights and overall understanding of the sulfur-metabolic processes in Acidithiobacillus spp. The future research directions and existing barriers in the bacterial sulfur metabolism are also emphasized here and the breakthroughs in these areas will accelerate the research on the sulfur oxidation in Acidithiobacillus spp. and other sulfur oxidizers.

Synthetic Fluororutaecarpine Inhibits Inflammatory Stimuli and Activates Endothelial Transient Receptor Potential Vanilloid-Type 1.

The natural product, rutaecarpine (RUT), is the main effective component of Evodia rutaecarpa which is a widely used traditional Chinese medicine. It has vasodilation, anticoagulation, and anti-inflammatory activities. However, further therapeutic applications are limited by its cytotoxicity. Thus, a derivative of RUT, 10-fluoro-2-methoxyrutaecarpine (F-RUT), was designed and synthesized that showed no cytotoxicity toward RAW264.7 macrophages at 20 µM. In an anti-inflammation experiment, it inhibited the production of nitric oxide (NO) and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages; cyclooxygenase (COX)-2 and inducible NO synthase (iNOS) induced by LPS were also downregulated. After 24 h of treatment, F-RUT significantly inhibited cell migration and invasion of ovarian A2780 cells. Furthermore, F-RUT promoted expressions of transient receptor potential vanilloid type 1 (TRPV1) and endothelial (e)NOS in human aortic endothelial cells, and predominantly reduced the inflammation in ovalbumin/alum-challenged mice. These results suggest that the novel synthetic F-RUT exerts activities against inflammation and vasodilation, while displaying less toxicity than its lead compound.

Lysosomal acid phosphatase 2 is an unfavorable prognostic factor but is associated with better survival in stage II colorectal cancer patients receiving chemotherapy.

Colorectal cancer (CRC) is one of the leading cancers worldwide. Surgery is the main therapeutic modality for stage II CRC. However, the implementation of adjuvant chemotherapy remains controversial and is not universally applied so far. In this study, we found that the protein expression of lysosomal acid phosphatase 2 (ACP2) was increased in CRC and that stage II CRC patients with high ACP2 expression showed a poorer outcome than those with low ACP2 expression (p = 0.004). To investigate this discrepancy, we analyzed the relation between ACP2 expression and several clinical cofactors.Among patients who received chemotherapy, those with an high expression of ACP2 showed better survival in both stage II and III CRC than those with low ACP2 expression. In stage II CRC patients, univariate analysis showed ACP2 expression and T stage to be cofactors significantly associated with overall survival (ACP2: p = 0.006; T stage: p = 0.034). Multivariate Cox proportion hazard model analysis also revealed ACP2 to be an independent prognostic factor for overall survival (ACP2: p = 0.006; T stage: p = 0.041). Furthermore, ACP2-knockdown CRC cells showed an increase in chemoresistance to 5-FU treatment and increased proliferation marker in the ACP2 knockdown clone.Taken together, our results suggested that ACP2 is an unfavorable prognostic factor for stage II CRC and may serve as a potential chemotherapy-sensitive marker to help identify a subset of stage II and III CRC patients for whom chemotherapy would improve survival.Highlights1. To the best of our knowledge, the study is the first report to show ACP2 overexpression in human colorectal cancer (CRC) and its association with poor outcome in stage II CRC.2. Patients with stage II and III CRCs with high expression of ACP2 were more sensitive to chemotherapy than those with a low expression.3. ACP2 expression may serve as a marker for CRC patients receiving chemotherapy and help identify the subset of CRC patients who would benefit from chemotherapy.

Multifunctions of Excited Gold Nanoparticles Decorated Artificial Kidney with Efficient Hemodialysis and Therapeutic Potential.

Chronic kidney disease (CKD) is inflammation-related. Patients with chronic renal failure who undergo hemodialysis (HD) have some acute adverse effects caused by dialysis-induced oxidative stress, protein adsorption, platelet adhesion, and activation of coagulation and inflammation. Here, resonantly illuminated gold nanoparticles-modified artificial kidney (AuNPs@AK) for achieving high efficiency accompanying therapeutic strategy for CKD during HD is proposed. The efficiency in removing uremic toxins increased obviously, especially in the presence of protein (closer to the real blood). The excited AuNPs@AK expressed negatively charged surface reduced some acute adverse effects caused by dialysis-induced protein adsorption, platelet adhesion, and activation of coagulation, thus avoiding thrombosis during HD. Unlike to traditional HD which provides only one function of removing uremic toxins, the solution collected from the outlet of the sample channel of excited AuNPs@AK showed an efficient free radical scavenger that could decrease dialysis-induced oxidative stress. In the CKD mouse model, this antioxidative solution from excited AuNPs@AK further decreased fibronectin expression and attenuated renal fibrosis, suggesting a reduced inflammatory response. These successful in vitro and in vivo approaches suggest that resonantly illuminated AuNPs@AK in HD take multiadvantages in shortening treatment time and reducing risk of adverse effects, which promise trailblazing therapeutic strategies for CKD.

Uteroplacental Insufficiency Alters the Retinoid Pathway and Lung Development in Newborn Rats.

BACKGROUND: Intrauterine growth retardation (IUGR) is associated with reduced lung function during infancy and perhaps throughout adulthood. The retinoic acid (RA) signaling pathway modulates pre- and postnatal lung development. This study was conducted to test our hypothesis that uteroplacental insufficiency alters the elements of the retinoid pathway in developing lungs. METHODS: On Gestation Day 18, either uteroplacental insufficiency was induced through bilateral uterine vessel ligation (IUGR group) or sham surgery (control group) was performed. Lung tissues from the offspring were examined through Western blotting, immunohistochemistry, and morphometry on Postnatal Day 3 and Postnatal Day 7. RESULTS: Compared with control rats, the IUGR rats exhibited significantly lower body weights on Postnatal Day 3 and Postnatal Day 7 and significantly lower lung weights on Postnatal Day 3. Uteroplacental insufficiency significantly increased RA receptor (RAR)-ß protein expression on Postnatal Day 3. The expression of RAR-α, RAR-γ, cellular RA-binding protein-1, and cellular RA-binding protein-2 between the control and IUGR rats was comparable on Postnatal Day 3 and Postnatal Day 7. Compared with the control rats, the IUGR rats exhibited a significantly higher volume fraction of alveolar airspace on Postnatal Day 3 and Postnatal Day 7 and a significantly lower volume fraction of alveolar walls on Postnatal Day 3. CONCLUSION: Uteroplacental insufficiency causes defective alveolarization and transient increases in RAR-ß expression in the lungs of newborn rats. The retinoid pathway may be one of the probable pathways mediating lung abnormalities caused by uteroplacental insufficiency.

Targeting of Topoisomerase I for Prognoses and Therapeutics of Camptothecin-Resistant Ovarian Cancer.

DNA topoisomerase I (TOP1) levels of several human neoplasms are higher than those of normal tissues. TOP1 inhibitors are widely used in treating conventional therapy-resistant ovarian cancers. However, patients may develop resistance to TOP1 inhibitors, hampering chemotherapy success. In this study, we examined the mechanisms associated with the development of camptothecin (CPT) resistance in ovarian cancers and identified evodiamine (EVO), a natural product with TOP1 inhibiting activity that overcomes the resistance. The correlations among TOP1 levels, cancer staging, and overall survival (OS) were analyzed. The effect of EVO on CPT-resistant ovarian cancer was evaluated in vitro and in vivo. TOP1 was associated with poor prognosis in ovarian cancers (p = 0.024). EVO induced apoptosis that was detected using flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The tumor size decreased significantly in the EVO treatment group compared with the control group (p < 0.01) in a xenograft mouse model. Effects of drugs targeting TOP1 for prognosis and therapy in CPT-resistant ovarian cancer are anticipated. EVO with TOP1 can be developed as an antiproliferative agent for overcoming CPT resistance in ovarian cancers.

Glucose biosensor based on glucose oxidase immobilized at gold nanoparticles decorated graphene-carbon nanotubes.

Biopolymer pectin stabilized gold nanoparticles were prepared at graphene and multiwalled carbon nanotubes (GR-MWNTs/AuNPs) and employed for the determination of glucose. The formation of GR-MWNTs/AuNPs was confirmed by scanning electron microscopy, X-ray diffraction, UV-vis and FTIR spectroscopy methods. Glucose oxidase (GOx) was successfully immobilized on GR-MWNTs/AuNPs film and direct electron transfer of GOx was investigated. GOx exhibits highly enhanced redox peaks with formal potential of -0.40 V (vs. Ag/AgCl). The amount of electroactive GOx and electron transfer rate constant were found to be 10.5 × 10(-10) mol cm(-2) and 3.36 s(-1), respectively, which were significantly larger than the previous reports. The fabricated amperometric glucose biosensor sensitively detects glucose and showed two linear ranges: (1) 10 µM - 2 mM with LOD of 4.1 µM, (2) 2 mM - 5.2 mM with LOD of 0.95 mM. The comparison of the biosensor performance with reported sensors reveals the significant improvement in overall sensor performance. Moreover, the biosensor exhibited appreciable stability, repeatability, reproducibility and practicality. The other advantages of the fabricated biosensor are simple and green fabrication approach, roughed and stable electrode surface, fast in sensing and highly reproducible.

Electrochemical OFF-ON ratiometric chemodosimeters for the selective and rapid detection of fluoride.

We have described two "OFF-ON electrochemical latent ratiometric redox chemodosimeters", 1,4-Bis(tert-butyldimethylsiloxy)benzene (H2Q') and 1,4-Bis (tert-butyldimet hylsiloxy)-2-methoxybenzene (MH2Q') for the selective detection of inorganic fluoride. The electrochemical signals of hydroquinone (H2Q) and o-methoxy hydroquinone (MH2Q) within this latent redox probes (H2Q' and MH2Q') were completely masked by protecting their hydroxyl group as silylether (OFF state). The externally added fluoride ions triggered the deprotection of H2Q' and MH2Q' and unmasked the electrochemical properties of H2Q and MH2Q respectively. The electrochemical reporters (H2Q and MH2Q) presented a pair of redox peaks at the electrode surface (ON state) and the peak currents are linearly dependent with the concentration of fluoride which leading to the ratiometric detection of fluoride. The limit of detection (signal-to-noise ratio=3) observed for the probes are 23.8 µM and 2.38 µM for H2Q' and MH2Q' respectively. The deprotection is highly selective for fluoride over other anions investigated. The probes are highly stable and the proposed approach offers rapid response time and promising practical applicability. The proposed strategy holds great promise for the commencement of new H2Q based electrochemical probes by tuning the electrochemical behavior of H2Q.

CFS-1686 causes cell cycle arrest at intra-S phase by interference of interaction of topoisomerase 1 with DNA.

CFS-1686 (chemical name (E)-N-(2-(diethylamino)ethyl)-4-(2-(2-(5-nitrofuran-2-yl)vinyl)quinolin-4-ylamino)benzamide) inhibits cell proliferation and triggers late apoptosis in prostate cancer cell lines. Comparing the effect of CFS-1686 on cell cycle progression with the topoisomerase 1 inhibitor camptothecin revealed that CFS-1686 and camptothecin reduced DNA synthesis in S-phase, resulting in cell cycle arrest at the intra-S phase and G1-S boundary, respectively. The DNA damage in CFS-1686 and camptothecin treated cells was evaluated by the level of ATM phosphorylation, γH2AX, and γH2AX foci, showing that camptothecin was more effective than CFS-1686. However, despite its lower DNA damage capacity, CFS-1686 demonstrated 4-fold higher inhibition of topoisomerase 1 than camptothecin in a DNA relaxation assay. Unlike camptothecin, CFS-1686 demonstrated no activity on topoisomerase 1 in a DNA cleavage assay, but nevertheless it reduced the camptothecin-induced DNA cleavage of topoisomerase 1 in a dose-dependent manner. Our results indicate that CFS-1686 might bind to topoisomerase 1 to inhibit this enzyme from interacting with DNA relaxation activity, unlike campothecin's induction of a topoisomerase 1-DNA cleavage complex. Finally, we used a computer docking strategy to localize the potential binding site of CFS-1686 to topoisomerase 1, further indicating that CFS-1686 might inhibit the binding of Top1 to DNA.

Maternal nicotine exposure exacerbates neonatal hyperoxia-induced lung fibrosis in rats.

BACKGROUND: Maternal nicotine exposure increases lung collagen in fetal and newborn animals. Connective tissue growth factor (CTGF) plays a role in hyperoxia-induced pulmonary fibrosis. OBJECTIVE: To determine whether pre- and postnatal nicotine exposure can augment CTGF expression and postnatal hyperoxia-induced lung fibrosis. METHODS: Nicotine was administered to pregnant Sprague-Dawley rats at a dose of 6 mg/kg/day from gestational days 7-21 (prenatal nicotine-treated group) and gestational day 7 to postnatal day 14 (pre- and postnatal nicotine-treated group). A control group of pregnant dams was injected with an equal volume of saline. Within 12 h of birth, rats were exposed to room air or 1 week of >95% O2 and an additional 2 weeks of 60% O2 (3 weeks of hyperoxia). Lungs were taken for total collagen, CTGF expression and histological analyses. RESULTS: In each maternal treatment group, the rats reared in hyperoxia had a higher total collagen compared with rats reared in room air on postnatal days 7 and 21. Collagen content was significantly higher in rats born to pre- and postnatal nicotine-treated dams than rats born to saline-treated and prenatal nicotine-treated dams on postnatal days 7 and 21. Pre- and postnatal nicotine exposure and neonatal hyperoxia exposure increased CTGF expression on postnatal days 7 and 21. CONCLUSIONS: CTGF may be involved in the pathogenesis of lung fibrosis induced by maternal nicotine and neonatal hyperoxia, and maternal nicotine exposure exacerbates neonatal hyperoxia-induced lung fibrosis. These results are relevant to neonates who require supplemental oxygen and are exposed to the breast milk of smoking mothers during infancy.

Innovative strategy with potential to increase hemodialysis efficiency and safety.

Uremic toxins are mainly represented by blood urine nitrogen (BUN) and creatinine (Crea) whose removal is critically important in hemodialysis (HD) for kidney disease. Patients undergoing HD have a complex illness, resulting from: inadequate removal of organic waste, dialysis-induced oxidative stress and membrane-induced inflammation. Here we report innovative breakthroughs for efficient and safe HD by using a plasmon-induced dialysate comprising Au nanoparticles (NPs)-treated (AuNT) water that is distinguishable from conventional deionized (DI) water. The diffusion coefficient of K3Fe(CN)6 in saline solution can be significantly increased from 2.76, to 4.62 × 10(-6) cm s(-1), by using AuNT water prepared under illumination by green light-emitting diodes (LED). In vitro HD experiments suggest that the treatment times for the removals of 70% BUN and Crea are reduced by 47 and 59%, respectively, using AuNT water instead of DI water in dialysate, while additionally suppressing NO release from lipopolysaccharide (LPS)-induced inflammatory cells.

Active and stable liquid water innovatively prepared using resonantly illuminated gold nanoparticles.

The properties of confined liquid water, or liquid water in contact with hydrophobic surfaces, are significantly different from those of bulk liquid water. However, all of water's commonly described properties are related to inert "bulk liquid water" which comprises a tetrahedral hydrogen-bonded network. In this work, we report an innovative and facile method for preparing small water clusters (SWCs) with reduced affinity hydrogen bonds by letting bulk water flow through supported Au nanoparticles (NPs) under resonant illumination to give NP-treated (AuNT) water at constant temperature. Utilizing localized surface plasmon resonance on illuminated Au NPs, the strong hydrogen bonds of bulk water can be disordered when water is located at the illuminated Au/water interface. The prepared SWCs are free of Au NPs. The energy efficiency for creating SWCs is ∼17%. The resulting stable AuNT water exhibits distinct properties at room temperature, which are significantly different from the properties of untreated bulk water, examples being their ability to scavenge free hydroxyl and 2,2-diphenyl-1-picrylhydrazyl radicals and to effectively reduce NO release from lipopolysaccharide-induced inflammatory cells.

The induction of heme oxygenase-1 suppresses heat shock protein 90 and the proliferation of human breast cancer cells through its byproduct carbon monoxide.

Heme oxygenase (HO)-1 is an oxidative stress-response enzyme which catalyzes the degradation of heme into bilirubin, ferric ion, and carbon monoxide (CO). Induction of HO-1 was reported to have antitumor activity; the inhibitory mechanism, however, is still unclear. In the present study, we found that treatment with [Ru(CO)3Cl2]2 (RuCO), a CO-releasing compound, reduced the growth of human MCF7 and MDA-MB-231 breast cancer cells. Analysis of growth-related proteins showed that treatment with RuCO down-regulated cyclinD1, CDK4, and hTERT protein expressions. Interestingly, RuCO treatment resulted in opposite effects on wild-type and mutant p53 proteins. These results were similar to those of cells treated with geldanamycin (a heat shock protein (HSP)90 inhibitor), suggesting that RuCO might affect HSP90 activity. Moreover, RuCO induced mutant p53 protein destabilization accompanied by promotion of ubiquitination and proteasome degradation. The induction of HO-1 by cobalt protoporphyrin IX (CoPP) showed consistent results, while the addition of tin protoporphyrin IX (SnPP), an HO-1 enzymatic inhibitor, diminished the RuCO-mediated effect. RuCO induction of HO-1 expression was reduced by a p38 mitogen-activated protein kinase inhibitor (SB203580). Additionally, treatment with a chemopreventive compound, curcumin, induced HO-1 expression accompanied with reduction of HSP90 client protein expression. The induction of HO-1 by curcumin inhibited 12-O-tetradecanoyl-13-acetate (TPA)-elicited matrix metalloproteinase-9 expression and tumor invasion. In conclusion, we provide novel evidence underlying HO-1's antitumor mechanism. CO, a byproduct of HO-1, suppresses HSP90 protein activity, and the induction of HO-1 may possess potential as a cancer therapeutic.

Low-cytotoxic synthetic bromorutaecarpine exhibits anti-inflammation and activation of transient receptor potential vanilloid type 1 activities.

Rutaecarpine (RUT), the major bioactive ingredient isolated from the Chinese herb Evodia rutaecarpa, possesses a wide spectrum of biological activities, including anti-inflammation and preventing cardiovascular diseases. However, its high cytotoxicity hampers pharmaceutical development. We designed and synthesized a derivative of RUT, bromo-dimethoxyrutaecarpine (Br-RUT), which showed no cytotoxicity at 20 µM. Br-RUT suppressed nitric oxide (NO) production and tumor necrosis factor-α release in concentration-dependent (0~20 µM) manners in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages; protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 induced by LPS were downregulated. Br-RUT inhibited cell migration and invasion of ovarian carcinoma A2780 cells with 0~48 h of treatment. Furthermore, Br-RUT enhanced the expression of transient receptor potential vanilloid type 1 and activated endothelial NOS in human aortic endothelial cells. These results suggest that the synthetic Br-RUT possesses very low cytotoxicity but retains its activities against inflammation and vasodilation that could be beneficial for cardiovascular disease therapeutics.