Spectroscopic investigation of photophysics and tautomerism of amino- and nitroporphycenes.

Parent, unsubstituted porphycene and its two derivatives: 2,7,12,17-tetra-n-propylporphycene and 2,7,12,17-tetra-t-butylporphycene were substituted at the meso position with amino and nitro groups. These two families of porphycenes were characterized in detail with respect to their spectral, photophysical, and tautomeric properties. Two trans tautomers of similar energies coexist in the ground electronic state, but only one form dominates in the lowest excited singlet state. Absorption, magnetic circular dichroism (MCD), and emission anisotropy combined with quantum-chemical calculations led to the assignment of S1 and S2 transitions in both tautomers. Compared with the parent porphycene, the S1-S2 energy gap significantly increases; for one tautomeric form, the effect is twice as large as for the other. Both amino- and nitroporphycenes emit single fluorescence; previously reported dual emission of aminoporphycenes is attributed to a degradation product. Introduction of bulky t-butyl groups leads to a huge decrease in fluorescence intensity; this effect, arising from the interaction of the meso substituent with the adjacent t-butyl moiety, is particularly strong in the nitro derivative.

Functionalization of filled radioactive multi-walled carbon nanocapsules by arylation reaction for in vivo delivery of radio-therapy.

Functionalized multi-walled carbon nanotubes (MWCNTs) containing radioactive salts are proposed as a potential system for radioactivity delivery. MWCNTs are loaded with isotopically enriched 152-samarium chloride (152SmCl3), the ends of the MWCNTs are sealed by high temperature treatment, and the encapsulated 152Sm is neutron activated to radioactive 153Sm. The external walls of the radioactive nanocapsules are functionalized through arylation reaction, to introduce hydrophilic chains and increase the water dispersibility of CNTs. The organ biodistribution profiles of the nanocapsules up to 24 h are assessed in naïve mice and different tumor models in vivo. By quantitative γ-counting, 153SmCl3@MWCNTs-NH2 exhibite high accumulation in organs without leakage of the internal radioactive material to the bloodstream. In the treated mice, highest uptake is detected in the lung followed by the liver and spleen. Presence of tumors in brain or lung does not increase percentage accumulation of 153SmCl3@MWCNTs-NH2 in the respective organs, suggesting the absence of the enhanced permeation and retention effect. This study presents a chemical functionalization protocol that is rapid (∼one hour) and can be applied to filled radioactive multi-walled carbon nanocapsules to improve their water dispersibility for systemic administration for their use in targeted radiotherapy.

The cognitive anxiety sensitivity treatment (CAST) in anxiety prevention - Focus on separation anxiety and interoception.

Given the high prevalence and considerable clinical and societal burden of anxiety disorders, preventive measures are urgently warranted to reduce their incidence and overall healthcare impact. Anxiety sensitivity (AS) - a key element in learning theories of anxiety disorders in the context of interoceptive conditioning - constitutes a malleable risk factor of particularly panic disorder and separation anxiety, which share developmental, nosological, epidemiological and pathomechanistic characteristics. The computer-assisted 'Cognitive Anxiety Sensitivity Treatment' (CAST) targeting interoceptive anxiety symptoms (cf. Schmidt et al., 2014) was translated, intensified and culturally adapted to German and evaluated in a sample of 105 healthy adult volunteers with elevated AS (mean ASI-3: 29.5) applying a randomized design. Success of the intervention was measured as a function of AS and separation anxiety (ASA-27) ∼6 weeks (T1) and ∼6 months (T2) after the intervention. As compared to waitlist, CAST resulted in a significant reduction of AS at both T1 and T2. Separation anxiety was not directly reduced by the intervention, but decreased mediated by a decline in AS. A composite interoceptive score capturing changes in sensitivity to respiratory symptoms during the baseline therapist-accompanied CAST session was shown to be predictive of overall response at T1. In sum, CAST-German Version was successfully established as an effective intervention reducing AS, while at the same time indirectly decreasing separation anxiety. A composite interoceptive score predicting treatment response might aid in further delineating risk markers informing targeted preventive interventions for anxiety disorders.

Comparison of the Effects of Resveratrol and Its Derivatives on the Radiation Response of MCF-7 Breast Cancer Cells.

Radiotherapy is among the most important methods for breast cancer treatment. However, this method's effectiveness is limited by radioresistance. The aim of this study was to investigate whether the stilbene derivatives piceid, resveratrol, and piceatannol have a radiosensitising effect on breast cancer cells (MCF-7). The conducted research enabled us to determine which of the tested compounds has the greatest potential in sensitising cells to ionising radiation (IR). Among the stilbene derivatives, resveratrol significantly increased the effect of IR. Resveratrol and IR used in combination had a higher cytotoxic effect on MCF-7 cells than using piceatannol, piceid, or radiation alone. This was due to a significant decrease in the activity of antioxidant enzymes, which resulted in the accumulation of formed reactive oxygen species (ROS). The effect of resveratrol and IR enhanced the expression of apoptotic genes, such as Bax, p53, and caspase 8, leading to apoptosis.

Transition from Simple V-V to V-A and Hybrid ECMO Configurations in COVID-19 ARDS.

In SARS-CoV-2 patients with severe acute respiratory distress syndrome (ARDS), Veno-Venous Extracorporeal Membrane Oxygenation (V-V ECMO) was shown to provide valuable treatment with reasonable survival in large multi-centre investigations. However, in some patients, conversion to modified ECMO support forms may be needed. In this single-centre retrospective registry, all consecutive patients receiving V-V ECMO between 1 March 2020 to 1 May 2021 were included and analysed. The patient cohort was divided into two groups: those who remained on V-V ECMO and those who required conversion to other modalities. Seventy-eight patients were included, with fourteen cases (18%) requiring conversions to veno-arterial (V-A) or hybrid ECMO. The reasons for the ECMO mode configuration change were inadequate drainage (35.7%), inadequate perfusion (14.3%), myocardial infarction (7.1%), hypovolemic shock (14.3%), cardiogenic shock (14.3%) and septic shock (7.1%). In multivariable analysis, the use of dobutamine (p = 0.007) and a shorter ICU duration (p = 0.047) predicted the conversion. The 30-day mortality was higher in converted patients (log-rank p = 0.029). Overall, only 19 patients (24.4%) survived to discharge or lung transplantation. Adverse events were more common after conversion and included renal, cardiovascular and ECMO-circuit complications. Conversion itself was not associated with mortality in the multivariable analysis. In conclusion, as many as 18% of patients undergoing V-V ECMO for COVID-19 ARDS may require conversion to advanced ECMO support.

The DNA methylome in panic disorder: a case-control and longitudinal psychotherapy-epigenetic study.

In panic disorder (PD), epigenetic mechanisms such as DNA methylation of candidate genes have been suggested to play a key role at the intersection of genetic and environmental factors. On an epigenome-wide level, however, only two studies in PD patients have been published so far, while to date no study has intra-individually analyzed dynamic epigenetic correlates of treatment-response in PD on a DNA methylome level. Here, an epigenome-wide association study (EWAS) was performed in a sample of 57 PD patients and matched healthy controls using the Illumina MethylationEPIC BeadChip, along with a longitudinal approach assessing changes on the DNA methylome level corresponding to clinical effects of a manualized six-week cognitive-behavioral therapy (CBT) in PD. While no epigenome-wide significant hits could be discerned, top suggestive evidence was observed for decreased methylation in PD at cg19917903 in the Cilia and Flagella Associated Protein 46 (CFAP46) gene, and for an increase in methylation after CBT at cg06943668 in the Interleukin 1 Receptor Type 1 (IL1R1) gene in treatment responders to CBT. Additional exploratory analyses based on biological validity and a combined statistical/biological ranking point to further new potential PD risk genes such as the CCL4L1 or GMNN genes, and suggest dynamic methylation of, e.g., the ZFP622 and the SLC43A2 genes along with response to CBT. These EWAS and first longitudinal epigenome-wide pilot data in PD add to the emerging candidate gene-based body of evidence for epigenetic mechanisms to be involved in PD pathogenesis and to possibly constitute dynamic biological correlates of therapeutic interventions.

Synthesis of sulfur containing macrocycles with sucrose scaffold.

The first synthesis of sucrose-based macrocycles containing two sulfur atoms in the ring was presented. The synthesis was initiated from known 6,6'-dideoxy-6,6'-di-chloro-1',2,3,3',4,4'-hexa-O-benzyl-sucrose in which both terminal positions (C6 and C6') were elongated by the -S-CH2-CH2-OH unit. The resulting diol was converted into dichloride and reacted further with a series of diamines which afforded the corresponding macrocyclic derivatives in high yields.

Cognitive-behavioral therapy effects on alerting network activity and effective connectivity in panic disorder.

Given the particular relevance of arousal and alerting in panic disorder (PD), here the alerting network was investigated (1) contrasting patients with PD and healthy controls, (2) as a function of anxiety sensitivity constituting a dimensional measure of panic-related anxiety, and (3) as a possible correlate of treatment response. Using functional magnetic resonance imaging (fMRI), 45 out-patients with PD (f = 34) and 51 matched healthy controls were investigated for brain activation patterns and effective connectivity (Dynamic Causal Modeling, DCM) while performing the Attention Network Task (ANT). Anxiety sensitivity was ascertained by the Anxiety Sensitivity Index (ASI). Forty patients and 48 controls were re-scanned after a 6 weeks cognitive-behavioral treatment (CBT) or an equivalent waiting time, respectively. In the alerting condition, patients showed decreased activation in fronto-parietal pathways including the middle frontal gyrus and the superior parietal lobule (MFG, SPL). In addition, ASI scores were negatively correlated with connectivity emerging from the SPL, the SFB and the LC and going to the MFG in patients but not in healthy controls. CBT resulted in an increase in middle frontal and parietal activation along with increased connectivity going from the MFG to the SPL. This change in connectivity was positively correlated with reduction in ASI scores. There were no changes in controls. The present findings point to a pathological disintegration of the MFG in a fronto-parietal pathway in the alerting network in PD which was observed to be reversible by a successful CBT intervention.

Epoxidation of Carbon Nanocapsules: Decoration of Single-Walled Carbon Nanotubes Filled with Metal Halides.

Methyl(trifluoromethyl)dioxirane (TFDO) can be used for the oxyfunctionalization of SWCNTs filled with NaI and LuCl3 under mild conditions. The chosen metal halides are of interest for theranostics, both for imaging and therapy when in their radioactive form. The applied functionalization methodology does not require metal catalyst, preserves the integrity of the nanotubes during treatment, avoiding the release of the filling material. In this way, epoxidation can be considered as an efficient methodology for the functionalization of carbon nanocapsules, where the traditional harsh oxidation conditions by acids are not applicable.

Shared and Distinct Cognitive/Affective Mechanisms in Intrusive Cognition: An Examination of Worry and Obsessions.

Generalized anxiety disorder and obsessive-compulsive disorder are defined by chronic intrusive thoughts. The aim of the present study was to evaluate the relationship between cognitive (attentional control) and motivational (negative urgency) mechanisms potentially underlying worry and obsessions. Participants (N = 526) completed an online questionnaire battery consisting of self-report measures of worry, OCD symptoms, attentional control (AC), negative urgency (NU), and trait negative affect. After controlling for trait negative affect, self-reported AC was negatively related to worry, repugnant obsessions, and ordering symptoms. Greater NU was associated with increased worry and repugnant obsessions. Further, self-reported AC and NU interacted such that greater NU was associated with greater worry at high but not low levels of AC. AC and NU were independently associated with repugnant obsessions. Perceived executive functioning impairments may confer risk for intrusive thoughts, particularly worries, whereas distress-driven impulsivity may contribute to the involuntary, ego-dystonic features of intrusions.

Effect of 3-bromopyruvate acid on the redox equilibrium in non-invasive MCF-7 and invasive MDA-MB-231 breast cancer cells.

Novel approaches to cancer chemotherapy employ metabolic differences between normal and tumor cells, including the high dependence of cancer cells on glycolysis ("Warburg effect"). 3-Bromopyruvate (3-BP), inhibitor of glycolysis, belongs to anticancer drugs basing on this principle. 3-BP was tested for its capacity to kill human non-invasive MCF-7 and invasive MDA-MB-231 breast cancer cells. We found that 3-BP was more toxic for MDA-MB-231 cells than for MCF-7 cells. In both cell lines, a statistically significant decrease of ATP and glutathione was observed in a time- and 3-BP concentration-dependent manner. Transient increases in the level of reactive oxygen species and reactive oxygen species was observed, more pronounced in MCF-7 cells, followed by a decreasing tendency. Activities of glutathione peroxidase, glutathione reductase (GR) and glutathione S-transferase (GST) decreased in 3-BP treated MDA-MB-231 cells. For MCF-7 cells decreases of GR and GST activities were noted only at the highest concentration of 3-BP.These results point to induction of oxidative stress by 3-BP via depletion of antioxidants and inactivation of antioxidant enzymes, more pronounced in MDA-MB-231 cells, more sensitive to 3-BP.

Nitroxides protect against peroxynitrite-induced nitration and oxidation.

Nitroxides are promising compounds for prevention of undesired protein modifications. The aim of this study was to compare the efficiency of 11 nitroxides, derivatives of 2,2,6,6-tetramethylpiperidine-1-oxide (TEMPO) and 2,2,5,5-tetramethylpirrolidine-1-oxyl (PROXYL) in prevention of nitration and oxidation of model compounds and human serum albumin (HSA). Most nitroxides were very efficient in preventing loss of fluorescein fluorescence induced by peroxynitrite (PN) (IC50 in the nanomolar range) and preventing HSA nitration. The loss of fluorescein fluorescence was demonstrated to be due to nitration. Nitroxides were more effective in prevention nitration than oxidation reactions. They showed a concentration window for preventing dihydrorhodamine (DHR) 123 oxidation but exerted a prooxidant effect at both high and low concentrations. No prooxidant effect of nitroxides was seen in prevention of DHR123 oxidation induced by SIN-1. In all essays hydrophobic nitroxides (especially 4-nonylamido-TEMPO and 3-carbamolyl-dehydroPROXYL) showed the lowest efficiency. An exception was the prevention of thiol group oxidation by PN and SIN-1 where hydrophobic nitroxides were the most effective, apparently due to binding to the protein. Nitroxides showed low toxicity to MCF-7 cells. Most nitroxides, except for the most hydrophobic ones, protected cells from the cytotoxic action of SIN-1 and SIN-1-induced protein nitration. These results point to potential usefulness of nitroxides for prevention of PN-induced oxidation and, especially, nitration.

Multilevel impact of the dopamine system on the emotion-potentiated startle reflex.

RATIONALE/OBJECTIVES: The pathogenetic mechanism of emotion-related disorders such as anxiety disorders is considered to be complex with an interaction of genetic, biochemical, and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic system-partly conferred by catechol-O-methyltransferase (COMT) gene variation-and for distorted emotional processing to constitute risk factors for anxiety and anxiety-related disorders. METHODS: Applying a multilevel approach, we analyzed the main and interactive effects of the functional COMT val158met polymorphism and L-dopa (single-dose 50 mg levodopa and 12.5 mg carbidopa; double-blind, placebo-controlled design) on the emotion-potentiated (unpleasant, neutral, and pleasant IAPS pictures) startle response as an intermediate phenotype of anxiety in a sample of 100 healthy probands (f = 52, m = 48). RESULTS: The COMT 158val allele was associated with an increased startle potentiation by unpleasant stimuli as compared with neutral stimuli irrespective of L-dopa or placebo intervention. COMT 158met/met genotype carriers, while displaying no difference in startle magnitude in response to unpleasant or neutral pictures in the placebo condition, showed startle potentiation by unpleasant pictures under L-dopa administration only. CONCLUSIONS: The present proof-of-concept study provides preliminary support for a complex, multilevel impact of the dopaminergic system on the emotion-potentiated startle reflex suggesting increased phasic dopamine transmission driven by the more active COMT 158val allele and/or a single dose of L-dopa to predispose to maladaptive emotional processing and thereby potentially also to anxiety-related psychopathological states.

Effect of functionalized and non-functionalized nanodiamond on the morphology and activities of antioxidant enzymes of lung epithelial cells (A549).

The development of nanotechnology opens up new ways for biomedical applications of unmodified and modified diamond nanoparticles which are one of the most popular nanomaterials used in biology, biotechnology, medicine, cosmetics and engineering. They have been applied as diagnostic and therapeutic agents because they can be targeted to and localized in cells causing apoptosis and necrosis. The problem of biocompatibility of nanodiamonds at higher concentrations is thus of primary importance. The first step in the modification of DNPs is usually the introduction of hydrogen groups, which can bind other functional groups. The basic method to introduce -OH groups onto nanoparticles is the Fenton reaction. The aim of this study was to compare the effect of unmodified nanodiamond particles and nanoparticles modified by introduction of -OH groups and etoposide onto their surface reaction on human non-small lung cancer cells. A549 cells were incubated with 2-100µg/ml nanopowders and at 0.6-24µg/ml etoposide in the DMEM medium. We observed a decrease of cells viability and generation of reactive oxygen/ nitrogen species in the cells after incubation, estimated by oxidation of H2DCF-DA and DAF-FM-DA. Modified detonation nanoparticles affected also the cellular content of glutathione and activities of main antioxidant enzymes (glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase and catalase). The results of TEM microscopy show changes in cell morphology. These data demonstrate that modified nanoparticles induce oxidative stress in the target cells.

Enhanced antioxidant capacity and anti-ageing biomarkers after diet micronutrient supplementation.

A growing number of studies confirm an important effect of diet, lifestyle and physical activity on health status, the ageing process and many metabolic disorders. This study focuses on the influence of a diet supplement, NucleVital®Q10 Complex, on parameters related to redox homeostasis and ageing. An experimental group of 66 healthy volunteer women aged 35-55 supplemented their diet for 12 weeks with the complex, which contained omega-3 acids (1350 mg/day), ubiquinone (300 mg/day), astaxanthin (15 mg/day), lycopene (45 mg/day), lutein palmitate (30 mg/day), zeaxanthine palmitate (6 mg/day), L-selenomethionine (330 mg/day), cholecalciferol (30 µg/day) and α-tocopherol (45 mg/day). We found that NucleVital®Q10 Complex supplementation significantly increased total antioxidant capacity of plasma and activity of erythrocyte superoxide dismutase, with slight effects on oxidative stress biomarkers in erythrocytes; MDA and 4-hydroxyalkene levels. Apart from the observed antioxidative effects, the tested supplement also showed anti-ageing activity. Analysis of expression of SIRT1 and 2 in PBMCs showed significant changes for both genes on a mRNA level. The level of telomerase was also increased by more than 25%, although the length of lymphocyte telomeres, determined by RT-PCR, remained unchanged. Our results demonstrate beneficial effects concerning the antioxidant potential of plasma as well as biomarkers related to ageing even after short term supplementation of diet with NucleVital®Q10 Complex.

Intracellular transport of nanodiamond particles in human endothelial and epithelial cells.

During the recent years nanodiamonds have been the subject of interest as possible means of targeted delivery of anticancer substances. Detonation nanodiamonds are attractive candidates for intracellular studies due to their synthesis methods, low cost, good biocompatibility and facile surface functionalizability. Our previous study, in which we used nanoparticles obtained by different methods showed the significance of size and way of production of nanodiamonds in their cellular effects. The aim of this study was to check the ability of surface-modified detonation nanodiamonds to reach intracellular compartments without degradation of the surface-conjugated drug or fluorescent marker. In this study we examined the penetration HUVEC-ST and A549 cells by detonation nanodiamonds (grain size <20 nm) modified by adding to, employing four pharmacological inhibitors of endocytosis, using optical, confocal and transmission electron microscopy We discuss the possibilities, the challenges of studying the endocytic pathways involved in cellular uptake of nanoparticles. Our results suggest that fluorescent nanomaterials are very promising for monitoring the intracellular fate of nanodiamonds.

Oxidative modification of blood serum proteins in multiple sclerosis after interferon or mitoxantrone treatment.

This study was aimed at (i) comparison of the usefulness of serum protein oxidation parameters for assessment of oxidative stress (OS) in multiple sclerosis (MS), and (ii) comparison of OS in MS patients subject to various therapies. Elevated glycophore level was noted in relapsing-remitting (RRMS) patients without treatment and patients treated with interferons ß1a and ß1b (10.33±3.27, 8.02±2.22 and 8.56±2.45 vs control 5.27±0.73 fluorescence units (FU)/mg protein). Advanced oxidation protein products (295±135 vs 83±65nmol/mg protein), carbonyl groups (3.68±1.44nmol/mg protein vs 2.03±0.23nmol/mg protein), kynurenine (7.71±0.1.67 vs 5.5±0.63 FU/mg protein) and N'-formylkynurenine (7.69±0.7 vs 4.97±0.59 FU/mg protein) levels were increased, while thioredoxin level was decreased in RRMS patients without treatment (5.03±2.18 vs 10.83±2.75ng/ml) with respect to control. The level of OS was higher in untreated RRMS patients and in SPMS patients treated with mitoxantrone than in patients treated with interferon.

Effects of ADORA2A gene variation and caffeine on prepulse inhibition: a multi-level risk model of anxiety.

The complex pathogenesis of anxiety and panic disorder in particular has been suggested to be influenced by genetic factors such as the adenosine A2A receptor gene (ADORA2A) 1976T>C polymorphism (rs5751876) as well as neuropsychological factors such as early information processing deficits. In 114 healthy individuals (males=57, females=57) controlled for anxiety sensitivity (AS), a multi-level risk model of the development of anxiety was applied: Genetic (ADORA2A 1976T>C variant) and biochemical (300 mg of caffeine citrate vs. placebo) factors were hypothesized to influence early information processing as measured by the prepulse inhibition/facilitation paradigm (stimulus onset asynchronies (SOAs) of 60, 120, 240, 480 and 2000ms between prepulses and startle stimuli). A fourfold interaction of genotype, intervention, gender, and SOAs was discerned. Stratification by SOAs revealed that at 120 ms and 240 ms SOAs in the caffeine condition, PPI was impaired in female ADORA2A 1976TT risk genotype carriers as compared to male ADORA2A 1976TT homozygotes, while no significant effects were observed in the ADORA2A 1976CC/CT non-risk genotype or placebo group. Only in high anxiety sensitive probands, a significant intervention effect was discerned with impaired prepulse facilitation (PPF) due to caffeine. The present results point to an impaired ability to selectively process very early information and to gate irrelevant sensory information, respectively, in female ADORA2A 1976TT homozygotes in response to caffeine, providing further evidence for the adenosinergic system to be involved in the pathogenesis of anxiety.

ADORA2A Gene variation, caffeine, and emotional processing: a multi-level interaction on startle reflex.

There is converging evidence for genetic, biochemical, and neuropsychological factors to increase the risk for anxiety and anxiety disorders. The pathogenesis of anxiety disorders is assumed to be influenced by a complex interaction of these individual risk factors on several levels, affecting intermediate phenotypes of anxiety such as the startle reflex. Thus, in the present double-blind, placebo-controlled study we attempted to paradigmatically investigate a multi-level pathogenetic model of anxiety by testing the effect of 300 mg caffeine citrate as an antagonist at the adenosine A2A receptor vs placebo on the emotion-potentiated (unpleasant, neutral, and pleasant International Affective Picture System pictures) startle reflex in 110 healthy individuals (male=56, female=54) stratified for the adenosine A2A receptor (ADORA2A) 1976T>C polymorphism (rs5751876). In addition to the expected main effect of picture category (highest startle amplitude for unpleasant, lowest for pleasant pictures) groups across all ADORA2A 1976T>C genotype and intervention (caffeine vs placebo) groups, an interaction effect of genotype, intervention, and picture category was discerned: In ADORA2A 1976TT risk genotype carriers, highest startle magnitudes were observed after caffeine administration in response to unpleasant pictures, with this effect arising particularly from the female subgroup. Our data point to a complex, multi-level, and potentially gender-specific pathogenetic model of anxiety, with genetic and biochemical factors interactively increasing the risk of maladaptive emotional processing and thereby possibly also anxiety disorders. The present findings may eventually aid in improving primary and secondary prevention by sharpening the risk profiles of anxiety-prone individuals.