Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class.

Here we describe a novel caged form of the highly reactive bioeffector molecule, nitroxyl (HNO). Reacting the labile nitric oxide (NO)- and HNO-generating salt of structure iPrHN-N(O)═NO(-)Na(+) (1, IPA/NO) with BrCH(2)OAc produced a stable derivative of structure iPrHN-N(O)═NO-CH(2)OAc (2, AcOM-IPA/NO), which hydrolyzed an order of magnitude more slowly than 1 at pH 7.4 and 37 °C.

The nitric oxide prodrug JS-K is effective against non-small-cell lung cancer cells in vitro and in vivo: involvement of reactive oxygen species.

Non-small-cell lung cancer is among the most common and deadly forms of human malignancies. Early detection is unusual, and there are no curative therapies in most cases. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics.

Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy.

Using an orthotopic model of renal cell carcinoma, we showed previously that IL-2/anti-CD40 immunotherapy resulted in synergistic anti-tumor responses, whereas IL-2 or α-CD40 alone mediated partial transient anti-tumor effects. We now show that treatment of tumor-bearing mice with IL-2/α-CD40, but not IL-2 or α-CD40, induced significant nitric oxide synthase (NOS) 2 expression in tumor-associated macrophages. In control-treated mice (low NO), NOS2 inhibition reduced tumor burden.

The role of self-efficacy in inflammatory bowel disease management: preliminary validation of a disease-specific measure.

Background: Inflammatory bowel diseases (IBDs) require self-management skills that may be influenced by self-efficacy (SE). Self-efficacy represents an individual's perception of his or her ability to organize and execute the behaviors necessary to manage disease. The goal of this study was to develop a valid and reliable measure of IBD-specific SE that can be used in clinical and research contexts.

A metaphor-enriched social cognition.

Social cognition is the scientific study of the cognitive events underlying social thought and attitudes. Currently, the field's prevailing theoretical perspectives are the traditional schema view and embodied cognition theories. Despite important differences, these perspectives share the seemingly uncontroversial notion that people interpret and evaluate a given social stimulus using knowledge about similar stimuli.

"Click" reaction in conjunction with diazeniumdiolate chemistry: developing high-load nitric oxide donors.

The use of Cu(I)-catalyzed "click" reactions of alkyne-substituted diazeniumdiolate prodrugs with bis- and tetrakis-azido compounds is described. The "click" reaction for the bis-azide using CuSO(4)/Na-ascorbate predominantly gave the expected bis-triazole. However, CuI/diisopropylethylamine predominantly gave uncommon triazolo-triazole products as a result of oxidative coupling.

JS-K, a nitric oxide-releasing prodrug, modulates ß-catenin/TCF signaling in leukemic Jurkat cells: evidence of an S-nitrosylated mechanism.

β-Catenin is a central player of the Wnt signaling pathway that regulates cell-cell adhesion and may promote leukemia cell proliferation. We examined whether JS-K, an NO-donating prodrug, modulates the Wnt/β-catenin/TCF-4 signaling pathway in Jurkat T-Acute Lymphoblastic Leukemia cells. JS-K inhibited Jurkat T cell growth in a concentration and time-dependent manner.

JS-K has potent anti-angiogenic activity in vitro and inhibits tumour angiogenesis in a multiple myeloma model in vivo.

Objectives: Glutathione S-transferases (GSTs) play an important role in multidrug resistance and are upregulated in multiple cancers. We have designed a prodrug class that releases nitric oxide on metabolism by GST. O(2)-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent antineoplastic activity.

Comparison between 3-Nitrooxyphenyl acetylsalicylate (NO-ASA) and O2-(acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA) as safe anti-inflammatory, analgesic, antipyretic, antioxidant prodrugs.

Chronic inflammation is an underlying etiological factor in carcinogenesis; nonsteroidal anti-inflammatory drugs (NSAIDs) and their chemically modified NO-releasing prodrugs (NO-NSAIDs) are promising chemopreventive agents. The aim of this study was to conduct a head-to-head comparison between two NO-ASAs possessing different NO donor groups, an organic nitrate [3-nitrooxyphenyl acetylsalicylate (NO-ASA; NCX-4016)] and an N-diazeniumdiolate [NONO-ASA, O(2)- (acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA; CVM-01)], as antiulcerogenic, analgesic, anti-inflammatory, and antipyretic agents. All drugs were administered orally at equimolar doses.

Broad-Spectrum Anti-Cancer Activity of O-Arylated Diazeniumdiolates.

O(2)-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) and O(2)-{2,4-dinitro-5-[4-(N-methylamino)be nzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO) are O(2)-arylated diazeniumdiolates that have shown promising in vivo activity in a variety of rodent cancer models, including prostate cancer, leukemia, liver cancer, multiple myeloma, and ovarian cancer. This compound class was designed to be activated for anti-cancer effects by glutathione-S-transferase (GST)-induced release of cytotoxic nitric oxide (NO), but mechanistic studies have implicated a variety of pathways, some GST/NO-related, some not. Current work is focused on improving formulations and other drug development activities, as well as exploring possible new applications of these agents and their analogs.

Nitrogen-bound diazeniumdiolated amidines.

In contrast to amidines bearing ionizable alpha-CH bonds, which react with nitric oxide (NO) to add diazeniumdiolate groups at their alpha-carbons, benzamidine forms an N-bound diazeniumdiolate that can be further derivatized at the other amidine nitrogen and/or the terminal oxygen to form caged NO compounds as potential NO prodrugs.

Insulin enhances the effect of nitric oxide at inhibiting neointimal hyperplasia in a rat model of type 1 diabetes.

Diabetes confers greater restenosis from neointimal hyperplasia following vascular interventions. While localized administration of nitric oxide (NO) is known to inhibit neointimal hyperplasia, the effect of NO in type 1 diabetes is unknown. Thus the aim of this study was to determine the efficacy of NO following arterial injury, with and without exogenous insulin administration.

The ties that bind: perceived social support, stress, and IBS in severely affected patients.

Background: This study assessed the association between social support and the severity of irritable bowel syndrome (IBS) symptoms in a sample of severely affected IBS patients recruited to an NIH-funded clinical trial. In addition, we examined if the effects of social support on IBS pain are mediated through the effects on stress.

Methods: Subjects were 105 Rome II diagnosed IBS patients (F = 85%) who completed seven questionnaires which were collected as part of a pretreatment baseline assessment.

Do patients with globus sensation respond to hypnotically assisted relaxation therapy? A case series report.

Globus sensation is a bothersome and difficult symptom to treat. The aims of this study were to evaluate the acceptability and utility of hypnotically-assisted relaxation (HAR) in decreasing the perception of globus sensation and the effect of HAR on interdeglutitive upper esophageal sphincter (UES) pressure. Sixteen subjects with persistent globus sensation unresponsive to therapy for reflux disease and with normal esophageal/laryngeal imaging studies were invited to participate in a 7-session clinical protocol.

A new approach to measuring estrogen exposure and metabolism in epidemiologic studies.

Endogenous estrogen plays an integral role in the etiology of breast and endometrial cancer, and conceivably ovarian cancer. However, the underlying mechanisms and the importance of patterns of estrogen metabolism and specific estrogen metabolites have not been adequately explored. Long-standing hypotheses, derived from laboratory experiments, have not been tested in epidemiologic research because of the lack of robust, rapid, accurate measurement techniques appropriate for large-scale studies.

Isopropylamine NONOate (IPA/NO) moderates neointimal hyperplasia following vascular injury.

Objective: Isopropylamine NONOate (IPA/NO) is a nitroxyl (HNO) donor at physiologic pH. HNO is a positive inotrope and vasodilator, but little is known about its effect on neointimal hyperplasia. The aims of this study are to determine the effect of IPA/NO on endothelial and vascular smooth muscle cells (VSMC) in vitro and to determine if IPA/NO inhibits neointimal hyperplasia in vivo.

Rapid response to cognitive behavior therapy predicts treatment outcome in patients with irritable bowel syndrome.

Background & Aims: Cognitive behavior therapy (CBT) is an empirically validated treatment for irritable bowel syndrome (IBS), yet it is unclear for whom and under what circumstances it is most effective. We investigated whether patients who achieved a positive response soon after CBT onset (by week 4), termed rapid responders (RRs), maintain treatment gains compared with non-rapid responders. We also characterized the psychosocial profile of RRs on clinically relevant variables (eg, health status, IBS symptom severity, distress).

Preliminary evidence supporting a framework of psychological adjustment to inflammatory bowel disease.

Background: Adjustment to chronic disease is a multidimensional construct described as successful adaptation to disease-specific demands, preservation of psychological well-being, functional status, and quality of life. Inflammatory bowel disease (IBD) can be particularly challenging due to the unpredictable, relapsing and remitting course of the disease.

Methods: All participants were patients being treated in an outpatient gastroenterology clinic at a university medical center.

Comparison of liquid chromatography-tandem mass spectrometry, RIA, and ELISA methods for measurement of urinary estrogens.

Absolute and relative concentrations of estrogens and estrogen metabolites are important for clinical decisions as well as for epidemiologic, experimental, and clinical research on hormonal carcinogenesis. RIA and ELISA are routinely used for measuring estrogen metabolites in blood and urine due to efficiency and low cost. Here, we compare absolute and ranked concentrations of estrone, estradiol, and estriol measured by indirect RIA and of 2-hydroxyestrone and 16alpha-hydroxyestrone measured by ELISA to the concentrations obtained using a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, which measures 15 estrogen metabolites concurrently.

Stabilization of the nitric oxide (NO) prodrugs and anticancer leads, PABA/NO and Double JS-K, through incorporation into PEG-protected nanoparticles.

We report the stabilization of the nitric oxide (NO) prodrugs and anticancer lead compounds, PABA/NO (O(2)-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) and "Double JS-K" 1,5-bis-{1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diol-2-ato}-2,4-dinitrobenzene, through their incorporation into polymer-protected nanoparticles. The prodrugs were formulated in block copolymer-stabilized nanoparticles with sizes from 220 to 450 nm by a novel rapid precipitation process. The block copolymers, with polyethylene glycol (PEG) soluble blocks, provide a steric barrier against NO prodrug activation by glutathione.

Glycosylated PROLI/NO derivatives as nitric oxide prodrugs.

GlcNAc-PROLI/NO prodrugs that are activated by N-acetylglucosaminidase to release nitric oxide (NO) are described. A classical acid-amine coupling is used to bifunctionalize these PROLI/NO prodrugs, which on activation generate up to 4 mol of NO, a peptide residue, and an N-acetylglucosamine residue. Many of the prodrugs synthesized are efficient sources of intracellular NO.

Soy intake is associated with increased 2-hydroxylation and decreased 16alpha-hydroxylation of estrogens in Asian-American women.

Introduction: In Asian and Asian-American women, soy consumption is associated with reduced breast cancer risk, perhaps due to its effects on estrogen production or metabolism. In a sample of Asian-American women, we investigated the associations of usual adult soy intake with the urinary concentrations of 15 estrogens and estrogen metabolites (EM) measured using liquid chromatography-tandem mass spectrometry.

Methods: Participants included 430 Chinese-American, Japanese-American, and Filipino-American women, ages 20 to 55 years, and living in San Francisco-Oakland (California), Los Angeles (California), or Oahu (Hawaii).

Structure mechanism insights and the role of nitric oxide donation guide the development of oxadiazole-2-oxides as therapeutic agents against schistosomiasis.

Schistosomiasis is a chronic parasitic disease affecting hundreds of millions of individuals worldwide. Current treatment depends on a single agent, praziquantel, raising concerns of emergence of resistant parasites. Here, we continue our explorations of an oxadiazole-2-oxide class of compounds we recently identified as inhibitors of thioredoxin glutathione reductase (TGR), a selenocysteine-containing flavoenzyme required by the parasite to maintain proper cellular redox balance.

Use of a new jumbo forceps improves tissue acquisition of Barrett's esophagus surveillance biopsies.

Background: The major risk factors for the development of esophageal adenocarcinoma remain long-standing GERD and resultant Barrett's esophagus (BE). Finding the exact method of adequate tissue sampling for surveillance of dysplasia in BE remains a dilemma.

Objective: We prospectively compared standard large-capacity biopsy forceps with a new jumbo biopsy forceps for dysplasia detection in BE.