Association of Heart Rate Variability with Obstructive Sleep Apnea in Adults.

Background and Objectives: Heart rate variability (HRV) analysis is a noninvasive method used to examine autonomic system function, and the clinical applications of HRV analysis have been well documented. The aim of this study is to investigate the association between HRV and the apnea-hypopnea index (AHI) in patients referred for polysomnography (PSG) for obstructive sleep apnea (OSA) diagnosis. Materials and Methods: Patients underwent whole-night PSG. Data on nocturnal HRV and AHI were analyzed. We determined the correlation of time- and frequency-domain parameters of HRV with the AHI. Results: A total of 62 participants (50 men and 12 women) were enrolled. The mean age, body mass index (BMI), neck circumference, and AHI score of the patients were 44.4 ± 11.5 years, 28.7 ± 5.2, 40.2 ± 4.8 cm, and 32.1 ± 27.0, respectively. The log root mean square of successive differences between normal heartbeats (RMSSD) were negatively correlated with BMI (p = 0.034) and neck circumference (p = 0.003). The log absolute power of the low-frequency band over high-frequency band (LF/HF) ratio was positively correlated with the AHI (p = 0.006). A higher log LF/HF power ratio (ß = 5.01, p = 0.029) and BMI (ß = 2.20, p < 0.001) were associated with a higher AHI value in multiple linear regression analysis. Conclusions: A higher log LF/HF power ratio and BMI were positively and significantly associated with the AHI during whole-night PSG in adult patients.

A data mining approach to investigate food groups related to incidence of bladder cancer in the BLadder cancer Epidemiology and Nutritional Determinants International Study.

At present, analysis of diet and bladder cancer (BC) is mostly based on the intake of individual foods. The examination of food combinations provides a scope to deal with the complexity and unpredictability of the diet and aims to overcome the limitations of the study of nutrients and foods in isolation. This article aims to demonstrate the usability of supervised data mining methods to extract the food groups related to BC. In order to derive key food groups associated with BC risk, we applied the data mining technique C5.0 with 10-fold cross-validation in the BLadder cancer Epidemiology and Nutritional Determinants study, including data from eighteen case-control and one nested case-cohort study, compromising 8320 BC cases out of 31 551 participants. Dietary data, on the eleven main food groups of the Eurocode 2 Core classification codebook, and relevant non-diet data (i.e. sex, age and smoking status) were available. Primarily, five key food groups were extracted; in order of importance, beverages (non-milk); grains and grain products; vegetables and vegetable products; fats, oils and their products; meats and meat products were associated with BC risk. Since these food groups are corresponded with previously proposed BC-related dietary factors, data mining seems to be a promising technique in the field of nutritional epidemiology and deserves further examination.

The association between coffee consumption and bladder cancer in the bladder cancer epidemiology and nutritional determinants (BLEND) international pooled study.

BACKGROUND: Inconsistent results for coffee consumption and bladder cancer (BC) risk have been shown in epidemiological studies. This research aims to increase the understanding of the association between coffee consumption and BC risk by bringing together worldwide case-control studies on this topic. METHODS: Data were collected from 13 case-control comprising of 5,911 cases and 16,172 controls. Pooled multivariate odds ratios (ORs), with corresponding 95% confidence intervals (CIs), were obtained using multilevel logistic regression models. Furthermore, linear dose-response relationships were examined using fractional polynomial models. RESULTS: No association of BC risk was observed with coffee consumption among smokers. However, after adjustment for age, gender, and smoking, the risk was significantly increased for never smokers (ever vs. never coffee consumers: ORmodel2 1.30, 95% CI 1.06-1.59; heavy (> 4 cups/day) coffee consumers vs. never coffee consumers: ORmodel2 1.52, 95% CI 1.18-1.97, p trend = 0.23). In addition, dose-response analyses, in both the overall population and among never smokers, also showed a significant increased BC risk for coffee consumption of more than four cups per day. Among smokers, a significant increased BC risk was shown only after consumption of more than six cups per day. CONCLUSION: This research suggests that positive associations between coffee consumption and BC among never smokers but not smokers.

A panel of tumor markers, calreticulin, annexin A2, and annexin A3 in upper tract urothelial carcinoma identified by proteomic and immunological analysis.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) is a tumor with sizable metastases and local recurrence. It has a worse prognosis than bladder cancer. This study was designed to investigate the urinary potential tumor markers of UTUC. METHODS: Between January 2008 and January 2009, urine was sampled from 13 patients with UTUC and 20 healthy adults. The current study identified biomarkers for UTUC using non-fixed volume stepwise weak anion exchange chromatography for fractionation of urine protein prior to two-dimensional gel electrophoresis. RESULTS: Fifty five differential proteins have been determined by comparing with the 2-DE maps of the urine of UTUC patients and those of healthy people. Western blotting analysis and immunohistochemistry of tumor tissues and normal tissues from patients with UTUC were carried out to further verify five possible UTUC biomarkers, including zinc-alpha-2-glycoprotein, calreticulin, annexin A2, annexin A3 and haptoglobin. The data of western blot and immunohistochemical analysis are consistent with the 2-DE data. Combined the experimental data in the urine and in tumor tissues collected from patients with UTUC, the crucial over-expressed proteins are calreticulin, annexin A2, and annexin A3. CONCLUSIONS: Calreticulin, annexin A2, and annexin A3 are very likely a panel of biomarkers with potential value for UTUC diagnosis.

Long-term benefits of a new oral appliance on adult snoring: a trend analysis.

Background: Snoring constitutes a worldwide public health concern that may be associated with daytime fatigue, endothelial dysfunction, vascular injury, stroke, cardiovascular diseases, and diabetes among female patients. This study explored the effects of the so-called Lin Oral Appliance (LOA) on Taiwanese adults' snoring rates. Methods: A time series analysis was conducted to examine the associations between LOAs' tongue compressors of different lengths, and snoring rates were calculated using the SnoreClock app. The LOA comprises 2 components: custom- made dental braces and tongue compressors of adjustable lengths; different versions had different-length compressors. Results: Our multiple linear regression time-series model revealed the effects of the LOA on snoring rates. The results indicated the following: i) LOA tongue compressor lengths of 1 and 2.5 cm (LOA-1 and LOA-2.5, respectively) were associated with reduced snoring rates; ii) sleep durations of 5.5-7.5 h and daytime sleepiness were associated with increased snoring rates; and iii) among participants with snoring rates above 10%, the snoring rates observed 1-7 days before a given day constituted a significant factor influencing snoring rates on the given day. Conclusions: We discovered that the LOA could reduce snoring rates and that the 2.5-cm compressor length in the LOA produced the best results.

Correlation between snoring sounds and obstructive sleep apnea in adults: a meta-regression analysis.

Objective: Snoring is a dominant clinical symptom in patients with obstructive sleep apnea (OSA), and analyzing snoring sounds might be a potential alternative to polysomnography (PSG) for the assessment of OSA. This study aimed to systematically examine the correlation between the snoring sounds and the apnea-hypopnea index (AHI) as the measures of OSA severity. Material and Methods: A comprehensive literature review using the MEDLINE, Embase, Cochrane Library, Scopus, and PubMed databases identified the published studies reporting the correlations between and severity of snoring and the AHI values by meta-regression analysis. Results: In total, 13 studies involving 3,153 adult patients were included in this study. The pooled correlation coefficient for snoring sounds and AHI values was 0.71 (95%CI: 0.49, 0.85) from the random-effects meta-analysis with the Knapp and Hartung adjustment. The I 2 and chi-square Q test demonstrated significant heterogeneity (97.6% and p<0.001). After adjusting for the effects of the other covariates, the mean value of the Fisher's r-to-z transformed correlation coefficient would have 0.80 less by the snoring rate (95%CI = -1.02, -0.57), 1.46 less by the snoring index (95%CI = -1.85, -1.07), and 0.21 less in the mean body mass index (95%CI = -0.31, -0.11), but 0.15 more in the mean age (95%CI = 0.10, 0.20). It fitted the data very well (R 2=0.9641). Conclusion: A high correlation between the severity of snoring and the AHI was found in the studies with PSG. As compared to the snoring rate and the snoring index, the snoring intensity, the snoring frequency, and the snoring time interval index were more sensitive measures for the severity of snoring.

Snoring Index and Neck Circumference as Predictors of Adult Obstructive Sleep Apnea.

Background. Snoring is the cardinal symptom of obstructive sleep apnea (OSA). The acoustic features of snoring sounds include intra-snore (including snoring index [SI]) and inter-snore features. However, the correlation between snoring sounds and the severity of OSA according to the apnea−hypopnea index (AHI) is still unclear. We aimed to use the snoring index (SI) and the Epworth Sleepiness Scale (ESS) to predict OSA and its severity according to the AHI among middle-aged participants referred for polysomnography (PSG). Methods. In total, 50 participants (mean age, 47.5 ± 12.6 years; BMI: 29.2 ± 5.6 kg/m2) who reported snoring and were referred for a diagnosis of OSA and who underwent a whole night of PSG were recruited. Results. The mean AHI was 30.2 ± 27.2, and the mean SI was 87.9 ± 56.3 events/hour. Overall, 11 participants had daytime sleepiness (ESS > 10). The correlation between SI and AHI (r = 0.33, p = 0.021) was significant. Univariate linear regression analysis showed that male gender, body mass index, neck circumference, ESS, and SI were associated with AHI. SI (ß = 0.18, p = 0.004) and neck circumference (ß = 2.40, p < 0.001) remained significantly associated with AHI by the multivariate linear regression model. Conclusion. The total number of snores per hour of sleep and neck circumference were positively associated with OSA among adults referred for PSG.

Effects of a novel oral appliance on snoring in adults: A pilot study.

ABSTRACTBACKGROUND/PURPOSE: Oral appliances (OAs) have been recommended as alternatives for adult patients with obstructive sleep apnea who are intolerant of continuous positive airway pressure therapy. The aim of this study was to explore the effect on snoring rates among adult patients through use of a novel OA termed the Lin OA (LOA, airflow-interference-type nasal congestion relieving and snore-ceasing oral appliance). MATERIALS AND METHODS: The LOA consist of two parts: dental braces and a fixed tongue compressor. The compressor lengths range from 0.5 cm to 3.5 cm across versions. Patients used the LOA during sleep and the SnoreClock smartphone application recorded their snoring rates. RESULTS: A total of 4920 recordings (4239 recordings from 34 men, 681 recordings from 8 women) were used for the analysis. The recordings were sorted in accordance with the applied length of the LOA tongue compressor (0.5-3.5 cm, LOA-0.5, LOA-1 and LOA-3.5), and participants not using the LOA were denoted as the LOA-0 group. The women had higher snoring rates in the LOA-0, LOA-0.5 to LOA-2 groups, but lower snoring rates in the LOA-3 group than men by the univariate analysis. The snoring rates were significantly reduced by a mean of 5.04% with every 1 cm increase in tongue compressor length. Continuous LOA use resulted in snoring rate reductions of 0.02% per day by the random intercept model of the linear regression. CONCLUSION: Use of this novel LOA may significantly reduce snoring rates by 5.04% with each 1 cm increase in tongue compressor length.

Family History and Risk of Bladder Cancer: An Analysis Accounting for First- and Second-degree Relatives.

Although evidence suggests that a positive family history of bladder cancer in first-degree relatives is an important risk factor for bladder cancer occurrence, results remain unclear. The influence of family history of nonbladder cancers and more distant relatives on bladder cancer risk is inconsistent. This research, therefore, aims to increase the understanding of the association between family history and bladder cancer risk based on worldwide case-control studies. In total 4,327 cases and 8,948 non-cases were included. Pooled ORs, with corresponding 95% confidence intervals (CI), were obtained using multilevel logistic regression models, adjusted by age, sex, ethnicity, smoking status, and smoking pack-years. The results show bladder cancer risk increased by having a first- or second-degree relative affected with bladder cancer (OR, 2.72; 95% CI, 1.55-4.77 and OR, 1.71; 95% CI, 1.22-2.40, respectively), and nonurologic cancers (OR, 1.61; 95% CI, 1.19-2.18). Moreover, bladder cancer risk increased by number of cancers affected first-degree relatives (for 1 and >1 first-degree relatives: OR, 1.42; 95% CI, 1.02-2.04; OR, 2.67; 95% CI, 1.84-3.86, respectively). Our findings highlight an increased bladder cancer risk for a positive bladder cancer family history in first- and second-degree relatives, and indicate a possible greater effect for an increment of numbers of affected relatives. PREVENTION RELEVANCE: This study found a positive association between family history and bladder cancer in first- and second-degree relatives, with an added effect attributed to smoking. Given the detriments of bladder cancer, at-risk individuals should receive family history screening and tobacco cessation and avoidance counseling.

Identification of low-abundance proteins via fractionation of the urine proteome with weak anion exchange chromatography.

BACKGROUND: Low-abundance proteins are difficultly observed on the two-dimensional gel electrophoresis (2-DE) maps of urine proteome, because they are usually obscured by high-abundance proteins such as albumin and immunoglobulin. In this study, a novel fractionation method was developed for enriching low-abundance proteins by removing high-abundance proteins and progressive elution with salts of various concentrations. RESULTS: Stepwise weak anion exchange (WAX) chromatography, which applied DEAE-Sephacel resin with non-fixed volume elution, was used to fractionate urine proteome prior to performing 2-DE. Urine proteome was separated into four fractions by progressively eluting the column with 0 M, 50 mM, 100 mM, and 1 M NaCl solutions. Most of the heavy and light immunoglobulin chains appeared in the eluent. After the high-abundance proteins were removed, various low-abundance proteins were enriched and could be easily identified. The potential of this method for obtaining diversified fractionations was demonstrated by eluting the column separately with Na2SO4 and MgCl2 solutions. The 2-DE maps of the fractions eluted with these different salt solutions of identical ionic strength revealed markedly different stain patterns. CONCLUSION: The present study demonstrated that this fractionation method could be applied for purposes of enriching low-abundance proteins and obtaining diversified fractionations of urine, and potentially other proteomes.

Synthesis and antiproliferative evaluation of certain indolo[3,2-c]quinoline derivatives.

The present report describes the synthesis and antiproliferative evaluation of certain indolo[3,2-c]quinoline derivatives. For the C(6) anilino-substituted derivatives, (11H-indolo[3,2-c]quinolin-6-yl)phenylamine (6a) was inactive. Structural optimization of 6a by the introduction of a hydroxyl group at the anilino-moiety resulted in the enhancement of antiproliferative activity in which the activity decreased in an order of para-OH, 7a>meta-OH, 8a>ortho-OH, 9a. For the C(6) alkylamino-substituted derivatives, 11a, 12a, 13a, 14a, and 15a exhibited comparable antiproliferative activities against all cancer cells tested and the skin Detroit 551 normal fibroblast cells. Three cancer cells, HeLa, A549, and SKHep, are very susceptible with IC(50) of less than 2.17 microM while PC-3 is relatively resistant to this group of indolo[3,2-c]quinolines. For the 2-phenylethylamino derivatives, compound 20a is active against the growth of HeLa with an IC(50) of 0.52 microM, but is less effective against the growth of Detroit 551 with an IC(50) of 19.32 microM. For the bis-indolo[3,2-c]quinolines, N,N-bis-[3-(11H-indolo[3,2-c]quinolin-6-yl)aminopropyl]amine hydrochloride (25) is more active than its N-methyl derivative 26 and the positive Doxorubicin. Mechanism studies indicated 25 can induce caspase-3 activation, gamma-H2AX phosphorylation, cleavage of poly(ADP-ribose)polymerase and DNA fragmentation. These results provide evidence that DNA, topo I, and topo II are the primary targets of indolo[3,2-c]quinoline derivatives and that consequently inhibits proliferation and causes apoptosis in cancer cells.

Involvement of c-Jun N-terminal kinase in G2/M arrest and FasL-mediated apoptosis induced by a novel indoloquinoline derivative, IQDMA, in K562 cells.

N'-(11H-Indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (IQDMA), an indoloquinoline derivative, synthesized in our laboratory, has been demonstrated to be an effective anti-tumor agent in human leukemia cells. Treatment of K562 cells with IQDMA resulted in G2/M phase cell cycle arrest, presumably involving the concomitant up-regulation of p21 and apoptosis through up-regulation of FasL and sequential activation of caspase-8 and caspase-3. In contrast to the lack of appreciable effect on the phosphorylation of ERK and p38 MAPK, activation of JNK was noted when K562 cells were exposed to IQDMA. Moreover, IQDMA-mediated G2/M phase arrest and apoptosis were reversed after treatment with the JNK-specific inhibitors, SP600125 and JNK inhibitor 1. Further investigation showed that SP600125 reduced the activation of FasL, caspase-3, caspase-8, and led to a marked decline of p21. Taken together, our data show that JNK plays an important role in IQDMA-mediated G2/M arrest and apoptosis of K562 cancer cells.

International pooled study on diet and bladder cancer: the bladder cancer, epidemiology and nutritional determinants (BLEND) study: design and baseline characteristics.

BACKGROUND: In 2012, more than 400,000 urinary bladder cancer cases occurred worldwide, making it the 7(th) most common type of cancer. Although many previous studies focused on the relationship between diet and bladder cancer, the evidence related to specific food items or nutrients that could be involved in the development of bladder cancer remains inconclusive. Dietary components can either be, or be activated into, potential carcinogens through metabolism, or act to prevent carcinogen damage. METHODS/DESIGN: The BLadder cancer, Epidemiology and Nutritional Determinants (BLEND) study was set up with the purpose of collecting individual patient data from observational studies on diet and bladder cancer. In total, data from 11,261 bladder cancer cases and 675,532 non-cases from 18 case-control and 6 cohort studies from all over the world were included with the aim to investigate the association between individual food items, nutrients and dietary patterns and risk of developing bladder cancer. DISCUSSION: The substantial number of cases included in this study will enable us to provide evidence with large statistical power, for dietary recommendations on the prevention of bladder cancer.

Synthesis and antiinflammatory evaluation of 9-anilinoacridine and 9-phenoxyacridine derivatives.

Mast cells, neutrophils, and macrophages are important inflammatory cells that have been implicated in the pathogenesis of acute and chronic inflammatory diseases. To explore a novel antiinflammatory agent, we have synthesized two types of acridines, 9-anilinoacridine and 9-phenoxyacridine derivatives, for evaluation on the grounds that acridine is a versatile heterocycle possessing a wide variety of biological properties. The title compounds were synthesized by reaction of 9-chloroacridine with appropriate Ar-NH(2) and Ar-OH, and their antiinflammatory activities on inhibitory effects on the activation of mast cells, neutrophils, and macrophages were studied. Three acridine derivatives 4, 10, and 11 were proved to be more potent than the reference inhibitor mepacrine for the inhibition of rat peritoneal mast cell degranulation with similar IC(50) values (16-21 microM). Compound 3 also showed potent inhibitory activity (IC(50) = 8.2 and 4.4 microM, respectively) for the secretion of lysosomal enzyme and beta-glucuronidase from neutrophils. Moreover, compounds 5 and 9 were shown to be efficacious inhibitors of TNF-alpha production in macrophage-like cell lines RAW 264.7. Compounds 2 and 12 were the potent inhibitors of TNF-alpha production in murine microglial cell lines N9. To further explore the cytotoxic properties of these acridine derivatives, (E)-12 was selected for NCI's in vitro disease-oriented tumor cells screen. The results indicated that this compound had no significant cytotoxicity with a mean GI(50) of 58.0 microM. These results indicated that the antiinflammatory effects of acridine derivatives were mediated, at least in part, through the suppression of chemical mediators released from mast cells, neutrophils, and macrophages and that these compounds have the potential to be novel antiinflammatory agents with no significant cytotoxicity.

The impact on sexual function after nerve sparing and non-nerve sparing radical retropubic prostatectomy.

BACKGROUND: We examine the impact of nerve sparing technique on the sexual function after radical retropubic prostatectomy for localized prostate cancer. METHODS: Between March, 1996 and September 2000, 44 men with clinically localized adenocarcinoma of the prostate who underwent radical retropubic prostatectomy (RRP) were included in this study. The mean age of these patients was 68.7 +/- 4.5 years old (range: 57-75). Among them, 8 patients were impotent preoperatively, 18 patients did not undergo nerve sparing surgery due to technical difficulties, and the remaining 18 potent patients underwent nerve sparing RRP. The postoperative sexual function was assessed by the International Index of Erectile Function (IIEF-6) and patient-reported percentage of recovery of sexual function. RESULTS: Mean length of follow-up was 14.4 +/- 2.7 months (range 12-18). The IIEF scores and % recovery of sexual function were significantly higher in nerve sparing surgery when compared to that of non-nerve sparing surgery (15.2 +/- 9.0 vs. 2.0 +/- 3.8 and 55 +/- 30% vs. 3 +/- 10%, respectively, p < 0.001). Of the 18 potent patients who underwent nerve sparing surgery, spontaneous erection and successful sexual activity was reported in 4 (22.2%) patients. Eight (44.4%) patients could achieve intercourse either with the aid of sildenafil or intracavernous alprostadil injection. Four (22.2%) patients had partial erection but refused further treatment. Two (11.1%) patients were completely impotent after nerve sparing surgery. Postoperative PSA was 0.10 +/- 0.18 (range 0.01-0.59). CONCLUSIONS: After a mean length of 14.4 months' follow-up, a majority of our patients could achieve sexual activity, and the cancer control following nerve sparing surgery was good. Our results suggest that nerve sparing retropubic radical prostatectomy is indicated in selected patients with localized adenocarcinoma of the prostate.

Intravesical stone formation several years after hysterectomy: a case report.

INTRODUCTION: Most bladder stones develop in patients with bladder outlet obstruction. Intravesical stone formation after surgery outside the urinary bladder is rare. CASE PRESENTATION: A 54-year-old Taiwanese woman with lower urinary tract symptoms following a hysterectomy 14 years ago presented to our hospital. The intravesical calculus had developed from non-absorbable sutures and hung on the dome of the urinary bladder. The stone and residuum of the suture were retrieved by performing an endoscopic procedure. CONCLUSIONS: The presence of an intravesical stone should be suspected in patients with a history of hysterectomy who have symptoms in the lower urinary tract. A hanging stone on the dome of the urinary bladder implies that suture materials migrate into the urinary bladder. The complication can be prevented by the routine use of absorbable material and double-checking with cystoscopy.

Identification of benzofuro[2,3-b]quinoline derivatives as a new class of antituberculosis agents.

A series of 11-alkoxylated and 11-aminated benzofuro[2,3-b]quinoline derivatives were designed, synthesized, and evaluated for their anti-TB and cytotoxic activities. The known 11-chlorobenzofuro[2,3-b]quinoline (3) was synthesized in a single step from anthranilic acid and 2-coumaranone in phosphorus oxychloride in 51% yield for the first time. Treatment of 3 with alcohols and amines gave 11-alkoxylated and 11-aminated benzofuro[2,3-b]quinoline derivatives respectively, which were evaluated for their anti-TB and cytotoxic activities. Our results indicated that 11-arylaminated derivatives were more active than their respective 11-aryloxylated isosteric isomers against Mycobacterium tuberculosis. Among the tested compounds, 11-methoxybenzofuro[2,3-b]quinoline (4), 11-methylamino- benzofuro[2,3-b]quinoline (9), and 11-dimethylaminobenzofuro[2,3-b]quinoline (14) exhibited significant activities against the growth of M. tuberculosis (MIC values of <0.20 microg/mL) and low cytotoxicities against VERO cell with IC(50) values of 11.77, 5.55, and >30.00 microg/mL respectively. The selectivity index (SI=IC(50)/MIC) for 4, 9, and 14 was greater than 58.85, 27.75, and 150 respectively.

Novel indoloquinoline derivative, IQDMA, induces G(2)/M phase arrest and apoptosis in A549 cells through JNK/p38 MAPK signaling activation.

AIMS: This study was performed to elucidate whether mitogen-activated protein kinases (MAPKs) are involved in the modulation of apoptosis and cell-cycle arrest by N'-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (IQDMA), in human lung adenocarcinoma A549 cells. MAIN METHODS: The effect of IQDMA on cell-cycle arrest and apoptosis was measured by flow cytometry, and phosphorylation levels of mitogen-activated protein kinases (MAPKs) and its regulatory molecules were studied by immunoblots. KEY FINDINGS: IQDMA-induced G(2)/M arrest was associated with a marked decrease in the protein expressions of cyclin A, cyclin B, and cyclin-dependent kinase (Cdk)1. IQDMA-induced apoptosis was accompanied with up-regulation of the protein expression of Bax and down-regulation of the protein levels of Bcl-2, Mcl-1, X-linked inhibitor of apoptosis (XIAP), and survivin, resulting in cytochrome c release and sequential activation of caspase-9 and caspase-3. IQDMA activated c-Jun N-terminal kinase (JNK), p38 MAPK (p38) and extracellular signal-regulated kinase (ERK) on A549 cells in a time-dependent manner. Unlike the ERK inhibitor (PD98059), inhibitors of JNK (SP600125) and p38 MAPK (SB203580) suppressed IQDMA-induced apoptosis and G(2)/M phase arrest in A549 cells. Both SP600125 and SB203580 attenuated the activation of Bax and cytochrome c release, and reversed down-regulation of Bcl-2, XIAP, survivin, cyclin A, cyclin B, and Cdk1 in IQDMA-treated cells. SIGNIFICANCE: These findings indicate that JNK/p38 MAPK pathways play an important role in IQDMA-induced G(2)/M arrest and apoptosis of A549 cells.

Synthesis and anti-osteoporotic evaluation of certain 3-amino-2-hydroxypropoxyisoflavone derivatives.

We report herein the synthesis and anti-osteoporotic evaluation of certain 3-amino-2-hydroxypropoxyisoflavone derivatives. The results indicated that 3-(3,4-dimethoxyphenyl)-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (4) and 3-{4-[3-(cyclohexylamino)-2-hydroxypropoxy]phenyl}-7-methoxy-4H-chromen-4-one (5a) exhibited significant inhibitory effects on osteoclast activity (TRAP activity in RAW 264.7 with an ED(50) of 0.56 and 2.28 microM respectively). Both compounds have also exhibited very strong osteogenic effects, approximately a 10-fold effect of Ipriflavone on mineralization of osteoblasts (MC3T3E1 cells, a preosteoblast cell line derived from calvaria of C57BL/6 mice). Results indicated the potency on enhancing mineralization in D1 cells (a bone marrow mesenchymal cell line derived from BALB/c mice) decreased in an order 4>Ipriflavone>5a. However, the potency on enhancing mineralization in human adipose tissue derived stem cells (hADSCs) decreased in an order 5a>4>Raloxifene>Ipriflavone. Compound 5a has been found to be non-cytotoxic and especially active in the enhancement of mineralization in human adipose tissue derived stem cells. Therefore, 5a was selected as a potential lead for further structural optimization.

Synthesis, cytotoxicity, and anti-inflammatory evaluation of 2-(furan-2-yl)-4-(phenoxy)quinoline derivatives. Part 4.

A number of 2-(furan-2-yl)-4-phenoxyquinoline derivatives have been synthesized and evaluated for anti-inflammatory evaluation. 4-[(2-Furan-2-yl)quinolin-4-yloxy]benzaldehyde (8), with an IC(50) value of 5.0 microM against beta-glucuronidase release, was more potent than its tricyclic furo[2,3-b]quinoline isomer 3a (>30 microM), its 4'-COMe counterpart 7 (7.5 microM), and its oxime derivative 13a (11.4 microM) and methyloxime derivative 13b (>30 microM). For the inhibition of lysozyme release, however, oxime derivative 12a (8.9 microM) and methyloxime derivative 12b (10.4 microM) are more potent than their ketone precursor 7 and their respective tricyclic furo[2,3-b]quinoline counterparts 4a and 4b. Among them, 4-[4-[(2-furan-2-yl)-quinolin-4-yloxy]phenyl]but-3-en-2-one (10) is the most active against lysozyme release with an IC(50) value of 4.6 microM, while 8 is the most active against beta-glucuronidase release with an IC(50) value of 5.0 microM. (E)-1-[3-[(2-Furan-2-yl)quinolin-4-yloxy]phenyl] ethanone oxime (11a) is capable of inhibiting both lysozyme and beta-glucuronidase release with IC(50) values of 7.1 and 9.5 microM, respectively. For the inhibition of TNF-alpha formation, 1-[3-[(2-furan-2-yl)quinolin-4-yloxy]phenyl]ethanone (6) is the most potent with an IC(50) value of 2.3 microM which is more potent than genistein (9.1 microM). For the inhibitory activity of fMLP-induced superoxide anion generation, 11a (2.7 microM), 11b (2.8 microM), and 13b (2.2 microM) are three of the most active. None of above compounds exhibited significant cytotoxicity.