Synthesis and biological evaluation of N‐acylated tyramine sulfamates containing C–F bonds as steroid sulfatase inhibitors

Steroid sulfatase (STS) is responsible for the hydrolysis of biologically inactive sulfated steroids into their active un‐sulfated forms and promotes the growth of various hormone‐dependent cancers (e.g., breast cancer). Therefore, the STS enzyme is a promising therapeutic target for the treatment of steroid‐sensitive cancers. Herein, we report the synthesis and biological evaluation of sulfamate analogs as potential STS inhibitors based on N‐acylated tyramines that contain C–F bonds. The inhibitory effects of the analogs were tested using STS isolated from human placenta. Of the analogs tested, 4‐(2‐perfluoroundecanoylaminoethyl)‐phenyl sulfamate, 5r , demonstrated the greatest inhibitory effect, with an IC₅₀ value of 2.18 μm (IC₅₀ value of 2.13 μm for coumarin‐7‐O‐sulfamate was used as a reference). These findings were supported by the results our computational analyses performed using molecular docking techniques.     

A Cardiovascular Health Intervention for Spanish Speakers: The Health Literacy and ESL Curriculum

Spanish speakers in the United States are in need of effective interventions that address both cardiovascular disease (CVD) and health literacy. However, the literature lacks interventions that have used and evaluated a strategies that focus on both, particularly at the community level. The aim of this study was to explore the effect of a health literacy curriculum on cardiovascular health behavior among Spanish speaking adults. It used a randomized controlled pre-posttest design. Participants included Hispanic adults with a low-to-intermediate level of English proficiency. The intervention group received the health literacy and English as a second language (ESL) Curriculum with CVD specific content, while the control group received a conventional ESL curriculum. Tools included the Spanish Cardiovascular Health Questionnaire (CSC), the test of functional health literacy in adults (TOFHLA), and the Combined English Language Skills Assessment. Analysis of change scores included independent sample t test and multiple linear regression. A total of 155 participants completed the study. There was a significant greater improvement for the intervention group in change of CSC score from pretest to posttest (P?=?0.049) compared to controls. The study also found significantly improved TOFHLA (P?=?0.011), however it did not find a relationship between changes in CVD behavior and health literacy or English proficiency. The Health Literacy and ESL Curriculum constitutes a valuable resource for addressing the cardiovascular health, literacy, and language needs of Spanish-speaking adults. Interventions that take a multilevel education and health approach may be more effective in addressing the needs of immigrants. Research should further explore the interactions between CVD behavior, health literacy, and English proficiency.     

Effectiveness of a Hospital-at-Home Integrated Care Program as Alternative Resource for Medical Crises Care in Older Adults With Complex Chronic Conditions

Objectives

To compare clinical outcomes in older patients with acute medical crises attended by a geriatrician-led home hospitalization unit (HHU) vs an inpatient intermediate-care geriatric unit (ICGU) in a post-acute care setting.

Ordinal response prediction using bootstrap aggregation,with application to a high‐throughput methylation data set

Many investigators conducting translational research are performing high‐throughput genomic experiments and then developing multigenic classifiers using the resulting high‐dimensional data set. In a large number of applications, the class to be predicted may be inherently ordinal. Examples of ordinal outcomes include tumor‐node‐metastasis (TNM) stage (I, II, III, IV); drug toxicity evaluated as none, mild, moderate, or severe; and response to treatment classified as complete response, partial response, stable disease, or progressive disease. While one can apply nominal response classification methods to ordinal response data, in doing so some information is lost that may improve the predictive performance of the classifier. This study examined the effectiveness of alternative ordinal splitting functions combined with bootstrap aggregation for classifying an ordinal response. We demonstrate that the ordinal impurity and ordered twoing methods have desirable properties for classifying ordinal response data and both perform well in comparison to other previously described methods. Developing a multigenic classifier is a common goal for microarray studies, and therefore application of the ordinal ensemble methods is demonstrated on a high‐throughput methylation data set. Copyright © 2009 John Wiley & Sons, Ltd.     

Induction of Apoptosis in HT-29 Cells by Extracts from Isothiocyanates-rich Varieties of Brassica Oleracea

Among the vegetables with anti-carcinogenic properties, members of the genus Brassica are the most effective at reducing the risk of cancer. This property may be explained by their principle bioactive compounds, isothiocyanates (ITCs). The aim of this study was to measure the amounts of ITCs in extracts from vegetables of the Brasssica genus and assay them for potency of induction of apoptosis in a colorectal cancer cell line (HT-29). ITCs were determined by the cyclocondensation assay with 1,2-benzenedithiol and induction of apoptosis by assessment of cell viability, caspase-3 activity and DNA fragmentation. Purple cabbage extract showed the highest ITC concentration per gram, fresh weight, followed by black cabbage and Romanesco cauliflower. At ITC concentrations of 7.08 μ g/mL these extracts decreased cell viability and induced caspase-3 and DNA fragmentation at 48h. Brussels sprouts showed the strongest effects on cell viability and caspase-3 activity. Varieties of Brassica Oleracea are rich sources of ITCs that potently inhibit the growth of colon cancer cells by inducting apoptosis. All the extracts showed anticancer activity at ITC concentrations of between 3.54 to 7.08 μ g/mL, which are achievable in vivo. Our results showed that ITC concentration and the chemopreventive responses of plant extracts vary among the varieties of Brassica Oleracea studied and among their cultivars.     

Pi*S and Pi*Z alpha 1 antitrypsin polymorphism and the risk for asbestosis in occupational exposure to asbestos

The effect of meso 2,3-dimercaptosuccinic acid (DMSA) and monoisoamyl DMSA (MiADMSA) on gallium arsenide (GaAs) induced liver damage was studied. The oral feeding rat model was used in this study. The animals were exposed to 10 mg/kg GaAs, orally, once daily, 5 days a week for 24 weeks and treated thereafter with single oral daily dose of either 0.3 mmol/kg DMSA or MiADMSA for two course of 5 days treatment. The animals were sacrificed thereafter. Lipid peroxidation was assessed by measuring liver thiobarbituric acid reactive substance (TBARS). Liver damage was assessed by number of biochemical variables and by light microscopy. The activity of superoxide dismutase (SOD) and delta-aminolevulinic acid dehydratase (ALAD) beside reduced glutathione (GSH) concentration was measured in blood. Exposure to GaAs produced a significant reduction in GSH while, increased the oxidized glutathione (GSSG) concentration. Hepatic glutathione peroxidase (GPx) and catalase activity increased significantly while level of serum transaminase increased moderately. Gallium arsenide exposure also produced marked hepatic histopathological lesions. Overall, treatment with MiADMSA proved to be better than DMSA in the mobilization of arsenic and in the turnover of some of the above mentioned GaAs sensitive biochemical alterations. Histopathological lesions also, responded more favorably to chelation treatment with MiADMSA than DMSA.     

A Study in First-Episode Psychosis Patients: Does Angiotensin I-Converting Enzyme Activity Associated With Genotype Predict Symptom Severity Reductions After Treatment With Atypical Antipsychotic Risperidone?

BackgroundOur previous studies showed increased angiotensin I-converting enzyme (ACE) activity in chronic schizophrenia patients compared with healthy control (HC) volunteers, and the relevance of combining ACE genotype and activity for predicting schizophrenia was suggested.MethodsACE activity was measured in plasma of ACE insertion/deletion (I/D) genotyped HC volunteers (n = 53) and antipsychotic-naïve first-episode psychosis (FEP) patients (n = 45) assessed at baseline (FEB-B) and also after 2 months (FEP-2M) of treatment with the atypical antipsychotic risperidone.ResultsACE activity measurements showed significant differences among HC, FEP-B, and FEP-2M groups (F = 5.356, df = 2, P = .005) as well as between HC and FEP-2M (post-hoc Tukey’s multiple comparisons test, P = .004). No correlation was observed for ACE activity increases and symptom severity reductions in FEP as assessed by total Positive and Negative Syndrome Scale (r = −0.131, P = .434). FEP subgrouped by ACE I/D genotype showed significant ACE activity increases, mainly in the DD genotype subgroup. No correlation between ACE activity and age was observed in FEP or HC groups separately (r = 0.210, P = .392), but ACE activity level differences observed between these groups were influenced by age.ConclusionsThe importance of measuring the ACE activity in blood plasma, associated with ACE I/D genotyping to support the follow-up of FEP patients, did not show correlation with general symptom amelioration in the present study. However, new insights into the influence of age and I/D genotype for ACE activity changes in FEP individuals upon treatment was demonstrated.     

Synthesis and biological evaluation of thiophosphate tricyclic coumarin derivatives as steroid sulfatase inhibitors

Steroid sulfatase (STS) enzyme inhibition is an important approach to the management of hormone-dependent breast cancer. In this paper, we report convenient methods for the synthesis and biological evaluation of thiophosphate tricyclic coumarin analogs exhibiting STS activity. The described methods are based on the straightforward preparation of 7-hydroxy-2,3-dihydro-1H-cyclopenta[c]chromen-2-one, 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one, and 3-hydroxy-8,9,10,11-tetrahydro-7H-cyclohepta[c]chromen-6-one and their further modification by the introduction of various thiophosphate moieties. The inhibition properties of the synthesized compounds were tested toward STS isolated from human placenta. Most of the new STS inhibitors possessed good to moderate activity toward STS. During the course of our investigation, the largest inhibitory effects in the STS enzyme assays were observed for the two compounds 3f and 4r, with IC₅₀ values of 13.3 and 30.3 μM, respectively (the IC₅₀ value of 1 μM for the 665-COUMATE was used as a reference). The structure–activity relationships of the synthesized coumarin derivatives toward STS enzymes are discussed.     

Functional analysis of gene expression in risperidone treated cells provide new insights in molecular mechanism and new candidate genes for pharmacogenetic studies

Risperidone is a potent antagonist of both dopamine and serotonin receptors. However, little is known about the underlying molecular mechanism by which risperidone acts. Although a number of genetic variants have been observed to correlate with treatment response there are no definitive predictors of response. We performed a genome-wide gene expression analysis (Human Genome U219 Array Plate) of a human neuroblastoma cell line (SK-N-SH) exposed to risperidone to identify molecular mechanisms involved in the cellular response to risperidone and thus identify candidate genes for pharmacogenetic studies. Our results revealed that cellular risperidone treatment is associated with a range of gene expression changes, which are time (6–48 h) and dose related (0.1–10 μM). We found that functional clusters of these changes correspond to Gene Ontology categories related to neural cell development functions, and synaptic structure and functions. We also identified Canonical Pathways related to these functional categories: neurogenesis and axon guidance; synaptic vesicle; and neurotransmitter signaling (dopamine, serotonin and glutamate). Finally, we identified candidate genes for pharmacogenetic studies related to the main risperidone secondary effects: motor disorders, cardiovascular disorders and metabolic disorders. Our results suggest that risperidone treatment affects the neurogenesis and neurotransmission of neuroblastoma cells, which is in agreement with the “initiation and adaptation” model to explain the mechanism of action of psychotropic drugs.     

Synthesis and Biological Evaluation of Fluorinated 3‐Phenylcoumarin‐7‐O‐Sulfamate Derivatives as Steroid Sulfatase Inhibitors

In the present work, we report the initial results of our study on a series of 3‐phenylcoumarin sulfamate‐based compounds containing C‐F bonds as novel inhibitors of steroid sulfatase. The new compounds are potent steroid sulfatase inhibitors, possessing more than 10 times higher inhibitory potency than coumarin‐7‐O‐sulfamate. In the course of our investigation, compounds 2b and 2c demonstrated the highest inhibitory effect on the enzymatic steroid sulfatase assay; both had IC₅₀ values of 0.27 μm (the IC₅₀ value of coumarin‐7‐O‐sulfamate is 3.5 μm , used as a reference).