Potassium tert-Butoxide-Promoted Tandem Cyclization of Organoselenium Alkynyl Aryl Propargyl Ethers.

Base-promoted cyclization of 3-organoselenyl-methylene-2-alkynyl aryl propargyl ethers has been developed for the synthesis of 3-butylselanyl-methylene benzofurans, 3-methyl-2-alkynyl-benzofurans, and 4-iodo-benzo[b]furan-fused selenopyrans. Under potassium tert-butoxide as the base and tetrahydrofuran as the solvent, at room temperature, 3-organoselenyl-methylene-2-alkynyl aryl propargyl ethers were converted into 3-butylselanyl-methylene benzofurans via a 5-exo-dig mode. Using the same substrate, changing the solvent to dimethylsulfoxide, 3-methyl-2-alkynyl-benzofurans were selectively obtained in good yields. From 3-butylselanyl-methylene benzofurans, 4-iodo-benzo[b]furan-fused selenopyrans were prepared through a nucleophilic cyclization promoted by molecular iodine. The optimization of the reaction conditions showed that the solvents governed the regioselectivity of this cyclization and the initial formation of the dimsyl anion by the reaction of dimethylsulfoxide with potassium tert-butoxide was crucial for the 3-methyl-2-alkynyl-benzofuran preparation. We also proposed the mechanism for the formation of the products, demonstrated that the methodology can be scaled up, and showed the application of the prepared compounds as substrate in further transformations.

Extent of non-adherence and non-persistence in asthma patients: analysis of a large claims data set.

OBJECTIVE: The objective of this study was to assess non-adherence (NA) and non-persistence (NP) to long-acting asthma medications in Germany by differentiating between measurement of NA in periods of therapy continuation and measurement of NP in therapy-naïve patients. METHODS: We analyzed treatment adherence to long-acting asthma medication using German claims data for periods of treatment continuation based on the medication possession ratio (MPR) and the proportion of days covered. Persistence was assessed in treatment-naïve patients. Outcomes were observed from the date of the first to the last prescription within a 12-month period. Both NA and NP analyses considered prescription supply, using either defined daily dosages, or prescribed daily dosages derived from a medical chart review. RESULTS: We identified 52,508 asthma patients (mean age: 40.1, 58.4% female) who received at least two long-acting asthma prescriptions within 12 months; 50,660 treatment-naïve patients were included in the NP analysis (mean age: 39.7, 58.8% female). The mean 12-month MPR was 38.5% (89.4% NA according to MPR ≤ 80%) and the average proportion of days covered was 40.4% (85.9% NA). Agent-specific MPR and NA rates varied between 31.8% (91.8% NA) and 56.2% (71.6% NA). The average weighted-MPR increased to 53.1% when using the prescribed daily dosage. Based on a > 90-day gap definition, 86.7% of patients were considered non-persistent after 12 months (>180: 72.3%). When using prescribed daily dosages, NP rates ranged from 66.7 to 78.5%. CONCLUSION: High levels of treatment NA and NP indicate a substantial need to improve adherence and persistence to long-acting asthma medication in Germany.

p-Chloro-diphenyl diselenide modulates Nrf2/Keap1 signaling and counteracts renal oxidative stress in mice exposed to repeated dexamethasone administrations.

Dexamethasone is a synthetic glucocorticoid that has been associated with oxidative stress in central and peripheral tissues. p-Chloro-diphenyl diselenide ((p-ClPhSe)2) is an antioxidant organoselenium compound. The present study evaluated whether nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap-1) signaling contributes to the (p-ClPhSe)2 antioxidant effects in the kidney of mice exposed to dexamethasone. Adult Swiss mice received dexamethasone (intraperitoneal) at a dose of 2 mg/kg or its vehicle for 21 days. After that, mice were treated with (p-ClPhSe)2 (intragastric) (1, 5, or 10 mg/kg) for 7 days. Samples of kidneys were collected for biochemical assays. (p-ClPhSe)2 at a dose of 1 mg/kg reversed the renal reactive oxygen species (ROS) and carbonyl protein (CP) levels increased by dexamethasone. (p-ClPhSe)2 at doses of 5 and 10 mg/kg was effective against the increase of thiobarbituric acid reactive substances, ROS, and CP, as well as the decrease of δ-aminolevulinic acid dehydratase activity and nonprotein sulfhydryl levels induced by dexamethasone. At 5 mg/kg, (p-ClPhSe)2 reduced the renal levels of 4-OH-2-HNE and heme oxygenase (HO-1), as well as modulated the Nrf2/Keap-1 signaling in mice exposed to dexamethasone. The present findings revealed that (p-ClPhSe)2 antioxidant effects were associated with the modulation of Nrf2/Keap-1 signaling pathway in the kidney of mice exposed to dexamethasone.

Echinocandins Accelerate Particle Transport Velocity in the Murine Tracheal Epithelium: Dependency on Intracellular Ca2+ Stores.

The mucociliary clearance of lower airways is modulated by different physiologic stimuli and also by pathophysiologic agents like polluting substances or pharmaceutical molecules. In the present investigation, we measured the particle transport velocity (PTV) of mouse tracheae as a surrogate for mucociliary clearance. In mouse tracheal preparations, we detected a sustained increase in the PTV under the application of the echinocandins caspofungin, anidulafungin, and micafungin. In further experiments, we observed the effects of echinocandins on the PTV were dependent on intracellular Ca2+ homeostasis. In Ca2+-free buffer solutions, the amplitude of the echinocandin-evoked rise in the PTV was significantly reduced relative to that in the experiments in Ca2+-containing solutions. Depletion of intracellular Ca2+ stores of the endoplasmic reticulum (ER) by caffeine completely prevented an increase in the PTV with subsequent caspofungin applications. Mitochondrial Ca2+ stores seemed to be unaffected by echinocandin treatment. We also observed no altered generation of reactive oxygen species under the application of echinocandins as probable mediators of the PTV. Consequently, the observed echinocandin effects on the PTV depend upon the Ca2+ influx and Ca2+ contents of the ER. We assume that all three echinocandins act intracellularly on ER Ca2+ stores to activate Ca2+-dependent signal transduction cascades, enhancing the PTV.

Swimming training mitigates the sex-specific hepatic disruption caused by a high-calorie diet: The putative modulation of Nrf2/Keap-1 pathway in male mice.

This study investigated whether swimming protocol induces adaptations to sex-specific oxidative stress and Nrf2/Keap-1 pathway in the liver of mice fed a high-calorie diet (HCD) during the early life period. Male and female Swiss mice were fed a standard or high-calorie (enriched with 20% lard and 20% corn syrup) diets, and the trained mice were subjected to a swimming protocol (5 days/week) from 21st to 49th postnatal days. Males fed a HCD had more pronounced alterations in all parameters evaluated than females. Although there was no increase in body weight, the fat deposition was higher in male mice exposed to diet. The intake of HCD induced dyslipidemia mainly in males. In a sex-dependent manner, the hepatic markers of oxidative damage, antioxidant defences, and a sensitive sulfhydryl protein were altered in mice fed a HCD. Swimming counteracted dyslipidemia, hepatic oxidative stress, and the Nrf2/Keap-1 signalling downregulation, in a sex-dependent manner, in mice exposed to a HCD. These findings demonstrate that a non-pharmacological therapy, swimming protocol, contributed to adaptations of sex-specific hepatic oxidative stress and Nrf2/Keap-1 regulation in male mice fed a HCD.

Circulating MicroRNAs as Potential Biomarkers for Lung Cancer.

Lung cancer is the number one cause of cancer-related mortality worldwide. To improve disease outcome, it is crucial to implement biomarkers into the clinics which assist physicians in their decisions regarding diagnosis, prognosis, as well as prediction of treatment response. Liquid biopsy offers an opportunity to obtain such biomarkers in a minimal invasive manner by retrieving tumor-derived material from body fluids of the patient. The abundance of circulating microRNAs is known to be altered in disease and has therefore been studied extensively as a cancer biomarker. Circulating microRNAs present a variety of favorable characteristics for application as liquid biopsy-based biomarkers, including their high stability, relatively high abundance, and presence is nearly all body fluids. Although the application of circulating microRNAs for the management of lung cancer has not entered the clinics yet, several studies showed their utility for diagnosis, prognosis, and efficacy prediction of various treatment strategies, including surgery, radio-/chemotherapy, as well as targeted therapy. To compensate for their limited tumor specificity, several microRNAs are frequently combined into microRNA panels. Moreover, the possibility to combine single microRNAs or microRNA panels with tumor imaging or other cancer-specific biomarkers has the potential to increase specificity and sensitivity and could lead to the clinical application of novel multi-marker combinations.

Photocontrolled DNA minor groove interactions of imidazole/pyrrole polyamides.

Azobenzenes are photoswitchable molecules capable of generating significant structural changes upon E-to-Z photoisomerization in peptides or small molecules, thereby controlling geometry and functionality. E-to-Z photoisomerization usually is achieved upon irradiation at 350 nm (π-π* transition), while the Z-to-E isomerization proceeds photochemically upon irradiation at >400 nm (n-π* transition) or thermally. Photoswitchable compounds have frequently been employed as modules, e.g., to control protein-DNA interactions. However, their use in conjunction with minor groove-binding imidazole/pyrrole (Im/Py) polyamides is yet unprecedented. Dervan-type Im/Py polyamides were equipped with an azobenzene unit, i.e., 3-(3-(aminomethyl)phenyl)azophenylacetic acid, as the linker between two Im/Py polyamide strands. Only the (Z)-azobenzene-containing polyamides bound to the minor groove of double-stranded DNA hairpins. Photoisomerization was exemplarily evaluated by 1H NMR experiments, while minor groove binding of the (Z)-azobenzene derivatives was proven by CD titration experiments. The resulting induced circular dichroism (ICD) bands of the bound ligands, together with the photometric determination of the dsDNA melting temperature, revealed a significant stabilization of the DNA upon association with the ligand. The (Z)-azobenzene acted as a building block inducing a reverse turn, which favored hydrogen bonds between the pyrrole/imidazole amide and the DNA bases. In contrast, the E-configured polyamides did not induce any ICD characteristic for minor groove binding. The incorporation of the photoswitchable azobenzene unit is a promising strategy to obtain photoswitchable Im/Py hairpin polyamides capable of interacting with the dsDNA minor groove only in the Z-configuration.

Diphenyl diselenide regulates Nrf2/Keap-1 signaling pathway and counteracts hepatic oxidative stress induced by bisphenol A in male mice.

Bisphenol A (BPA) is a chemical toxicant that has deleterious effects on human. BPA causes oxidative stress in tissues, including the liver. Diphenyl diselenide (PhSe)2 improves the antioxidant response via activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein (keap 1) pathway in macrophage cells. In the present study, we investigated whether (PhSe)2 counteracts hepatic oxidative stress induced by BPA in male and female Swiss mice. Three-week-old mice received by the intragastric (i.g.) route BPA (5 mg/kg) from 21st to 60th postnatal day (PND). At PND 61, the mice were treated with (PhSe)2 (1 mg/kg, i.g.) for seven days. Parameters of hepatic damage and oxidative stress were determined in male and female mice. The results show that BPA increased the activity of aspartate aminotransferase in female mice, and in male mice the activity of alanine aminotranseferase was increased. Male and female mice had an increase in fat mass accumulation. Male mice showed an increase in hepatic oxidative damage of proteins and a decrease in non-enzymatic (ascorbic acid and non-protein thiol) and enzymatic (superoxide dismutase) defenses, which are consistent with oxidative stress status. Male mice were more susceptible than female mice to hepatic oxidative stress induced by BPA. BPA decreased Nrf2/Keap1 protein content in male mice. (PhSe)2 reduced hepatic oxidative stress induced by BPA in male mice. Our results demonstrate that male mice were more susceptible to hepatic oxidative stress induced by BPA than female mice. (PhSe)2 regulated Nrf2/Keap-1 signaling pathway and countered hepatic oxidative stress induced by BPA in male mice.

TREATMENT OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION PATIENTS WITH VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS IN EVERYDAY PRACTICE: Identification of Health Care Constraints in Germany-The PONS Study.

PURPOSE: The PONS study was conceived to analyze the extent of nonpersistence (NP) and nonadherence (NA) in the treatment of patients with neovascular age-related macular degeneration in everyday clinical practice in Germany. Further objectives were to identify factors that can affect NP and NA and to analyze clinical outcomes under everyday conditions. METHODS: Nonpersistence (no contact with doctor for at least 3 months) and NA (no treatment or follow-up for at least 6 weeks) as well as clinical data were analyzed up to 24 months retrospectively and 12 months prospectively in 480 patients with neovascular age-related macular degeneration in 23 treatment centers. Patients were interviewed for factors possibly affecting NP and NA. RESULTS: One third of patients fulfilled criteria of NA in the first 3 months and two thirds after 6 months. The NP was 18.8% after 12 months. Treatment exclusively at one center, a higher number of patients with neovascular age-related macular degeneration at the treating center, and fixed appointments were associated with a lower risk for NP. An initial gain in visual acuity after upload was not preserved after 12 months (mean change -0.5 Early Treatment Diabetic Retinopathy Study letters). Whereas visual acuity declined by 7.5 Early Treatment Diabetic Retinopathy Study letters in patients with good baseline visual acuity >20/40, visual acuity improved by 8.5 letters in patients with baseline visual acuity of ≤20/200. Only 7.5% of patients underwent an optical coherence tomography scan after 3 upload injections, and only 2.0 optical coherence tomographies were performed in the first 12 months. CONCLUSION: The NP and NA were high in our study population and are likely to have contributed to a suboptimal clinical outcome compared with randomized clinical trials. Shortcomings in the management of patients with neovascular age-related macular degeneration, including restrictions in the timely and adequate follow-up (including optical coherence tomography) and retreatment, appear to be constraining factors in Germany.

[Family relations and behavioral-emotional problems in adolescents - an analysis with the adolescent version of the Family Relations Test for Children and Adolescents]. / Familienbeziehungen und psychische Auffälligkeiten im Jugendalter ­ eine Analyse mit der Jugendlichenfassung des Family Relations Test für Kinder und Jugendliche.

Family relations and behavioral-emotional problems in adolescents - an analysis with the adolescent version of the Family Relations Test for Children and Adolescents Abstract. OBJECTIVES: So far hardly any instruments are available for the German-speaking countries, covering family relations from the perspective of young people reliably. Moreover, the relationship between family relations from the perspective of young people and behavioral problems has been rarely investigated. METHOD: Based on the Family Relations Test, which has been developed originally for children, the Family Relations Test for Children and Adolescents was developed in order to assess the family relations from the perspective of adolescents (94 items, 44 % newly developed). A clinical sample (n = 152) and a field sample (n = 132) was tested with this instrument and additionally behavioural problems of the adolescents were rated by the parents and the adolescents. RESULTS: The two-factor solution of the principal component analysis resulted in a clear distinction between two factors describing positive and negative family relations. The internal consistencies (Cronbach's Alpha) of the scales describing positive and negative relations are between .91 and .93. On these total scores young people from the clinic sample describe overall stronger negative relations in their families compared to young people in the field sample. Within the clinic sample moderate correlations between the extent of mental problems of young people rated by themselves and their parents could be found. CONCLUSIONS: Positive and negative relationships of young people to the individual family members and to all members of the family as a whole can be assessed reliably and factorially valid. As expected, significant correlations between negative family relations and mental problems could be found. The adolescent version of the Family Relations Test for Children and Adolescents proves to be a useful tool, to assess family relationships from the perspective of young people and thus to identify possible factors maintaining mental disorders of young people.