Bifunctional Sildenafil Diazeniumdiolates Acting as Phosphodiesterase 5 Inhibitors and Nitric Oxide Donors- Towards Wound Healing.

Inefficient wound healing poses a global health challenge with a lack of efficient treatments. Wound healing issues often correlate with low endogenous nitric oxide (NO) levels. While exogenous delivery with NO-releasing compounds represents a promising therapeutic strategy, controlling the release of the highly reactive NO remains challenging. Phosphodiesterase 5 (PDE5) inhibitors, like sildenafil, have also been shown to promote wound healing. This study explores hybrid compounds, combining NO-releasing diazeniumdiolates with a sildenafil-derived PDE5 inhibitor. One compound demonstrated a favorable NO-release profile, triggered by an esterase (prodrug), and displayed in vitro nanomolar inhibition potency against PDE5 and thrombin-induced platelet aggregation. Both factors are known to promote blood flow and oxygenation. Thus, our findings unveil promising prospects for effective wound healing treatments.

Total 25-Hydroxyvitamin D Is an Independent Marker of Left Ventricular Ejection Fraction in Heart Failure with Reduced and Mildly Reduced Ejection Fraction.

Vitamin D emerged as an important prognostic biomarker in heart failure (HF), with currently highly debated therapeutic implications. Several trials on vitamin D supplementation in HF showed improvements in left ventricular (LV) remodeling and function and health-related quality of life (HRQoL), which did not translate into mid- to long-term beneficial effects regarding physical performance and mortality. We addressed total 25-hydroxyvitamin D (25(OH)D), serum albumin, and uric acid (UA) levels, focusing mainly on vitamin D deficiency, as potential markers of LV systolic dysfunction in HF with reduced and mildly reduced ejection fraction (HFrEF, HFmrEF). Seventy patients with LVEF < 50% were comprehensively evaluated using ECG, echocardiography, lung ultrasound (LUS), blood sampling, and the six-minute walk test (6MWT). HRQoL was also assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Statistically significant positive correlations were found between LVEF, 25(OH)D, serum UA, and albumin, respectively (p = 0.008, p = 0.009, and p = 0.001). Serum UA (7.4 ± 2.4 vs. 5.7 ± 2.1, p = 0.005), NT-proBNP levels (1090.4 (675.2-2664.9) vs. 759.0 (260.3-1474.8), p = 0.034), and MLHFQ scores (21.0 (14.0-47.0) vs. 14.5 (4.5-25.5), p = 0.012) were significantly higher, whereas 25(OH)D concentrations (17.6 (15.1-28.2) vs. 22.7 (19.5-33.8), p = 0.010) were lower in subjects with severely reduced LVEF. Also, 25(OH)D was independently associated with LVEF in univariate and multiple regression analysis, maintaining its significance even after adjusting for confounders such as age, NT-proBNP, the presence of chronic coronary syndrome, hypertension, and anemia. According to our current findings, 25(OH)D is closely associated with LVEF, further supporting the need to establish correct vitamin D supplementation schemes and dietary interventions in HF. The changes in LVEF, 25(OH)D, serum UA, and albumin levels in HFrEF and HFmrEF indicate a similar pathophysiological background.

Association of Depression and Anxiety with Cardiac Structural and Functional Characteristics in Heart Failure with Reduced and Mildly Reduced Ejection Fraction.

Heart failure and mental health conditions frequently coexist and have a negative impact on health-related quality of life and prognosis. We aimed to evaluate depression and anxiety symptoms and to determine the association between psychological distress and cardiac parameters in heart failure with reduced and mildly reduced ejection fraction. A total of 43 patients (33 male, mean age 64 ± 10 years) with heart failure and left ventricular systolic dysfunction (29 with HFrEF, 14 with HFmrEF) underwent comprehensive echocardiographic evaluation. All study participants completed questionnaires for the assessment of depression (PHQ-9), anxiety (GAD-7), and health-related quality of life (MLHFQ). Ten (34%) patients with HFrEF and two (14%) participants with HFmrEF had moderate-to-severe depression symptoms. Significant anxiety symptoms were more frequent in HFrEF (10 vs. 2 patients; 34% vs. 14%). Poor quality of life was also more common among patients with HFrEF (17 vs. 5 patients; 59% vs. 36%), showing higher MLHFQ scores (p = 0.009). Moreover, PHQ-9, GAD-7, and MLHFQ scores showed significant correlations between NYHA class severity and the presence of peripheral edema. The symptoms of dyspnea correlated with both PHQ-9 and MLHFQ scores. Significant correlations were observed between MLHFQ scores and a large number of clinical features, such as exercise capacity, 6MWT distance, the need for furosemide, echocardiographic parameters (LVEDVI, LVESVI, LVEF, LVGLS, SVI), and laboratory variables (albumin, GFR, NT-proBNP). In the multiple linear regression analysis, dyspnea proved to be a significant predictor of higher PHQ-9 and MLHFQ scores, even after adjusting for potential confounders. High symptom burden due to psychological distress is common among patients with HFrEF and HFmrEF. More efficient control of congestion may improve depression, anxiety symptoms, and health-related quality of life.

Helsmoortel-Van der Aa Syndrome-Cardiothoracic and Ectodermal Manifestations in Two Patients as Further Support of a Previous Observation on Phenotypic Overlap with RASopathies.

The ADNP-gene-related neurodevelopmental disorder Helsmoortel-Van der Aa syndrome is a rare syndromic-intellectual disability-an autism spectrum disorder first described by Helsmoortel and Van der Aa in 2014. Recently, a large cohort including 78 patients and their detailed phenotypes were presented by Van Dijck et al., 2019, who reported developmental delay, speech delay and autism spectrum disorder as nearly constant findings with or without variable cardiological, gastroenterological, urogenital, endocrine and neurological manifestations. Among cardiac malformations, atrial septal defect, patent ductus arteriosus, patent foramen ovale and mitral valve prolapse were the most common findings, but other unspecified defects, such as mild pulmonary valve stenosis, were also described. We present two patients with pathogenic ADNP variants and unusual cardiothoracic manifestations-Bland-White-Garland syndrome, pectus carinatum superiorly along the costochondral junctions and pectus excavatum inferiorly in one patient, and Kawasaki syndrome with pericardiac effusion, coronary artery dilatation and aneurysm in the other-who were successfully treated with intravenous immunoglobulin, corticosteroid and aspirin. Both patients had ectodermal and/or skeletal features overlapping those seen in RASopathies, supporting the observations of Alkhunaizi et al. 2018. on the clinical overlap between Helsmoortel-Van der Aa syndrome and Noonan syndrome. We observed a morphological overlap with the Noonan-like disorder with anagen hair in our patients.

Cor Triatriatum Sinister Presenting as Cardioembolic Stroke in a Young Woman.

Cor triatriatum sinister is a rare congenital heart disease characterized by an additional fibromuscular membrane in the left atrium. Cardioembolic stroke is a rare complication of cor triatriatum sinister, especially among women. We hereby describe the case of an 18-year-old female patient, without a past medical history, presenting with cardioembolic stroke in the territory of the right posterior cerebral artery. During extensive diagnostic work-up, nonrestrictive cor triatriatum sinister and patent foramen ovale were diagnosed using transthoracic and transesophageal echocardiography. In clinical practice, it is important to identify congenital cardiac defects as potential substrates for cardioembolism in young patients. In our case, cor triatriatum sinister presenting as ischemic stroke was diagnosed, which is an uncommon finding, especially in young females. Determining the optimal management strategy for patients with cor triatriatum sinister complicated by cardioembolic stroke requires a multidisciplinary approach.

Targeting Mediators of Inflammation in Heart Failure: A Short Synthesis of Experimental and Clinical Results.

Inflammation has emerged as an important contributor to heart failure (HF) development and progression. Current research data highlight the diversity of immune cells, proteins, and signaling pathways involved in the pathogenesis and perpetuation of heart failure. Chronic inflammation is a major cardiovascular risk factor. Proinflammatory signaling molecules in HF initiate vicious cycles altering mitochondrial function and perturbing calcium homeostasis, therefore affecting myocardial contractility. Specific anti-inflammatory treatment represents a novel approach to prevent and slow HF progression. This review provides an update on the putative roles of inflammatory mediators involved in heart failure (tumor necrosis factor-alpha; interleukin 1, 6, 17, 18, 33) and currently available biological and non-biological therapy options targeting the aforementioned mediators and signaling pathways. We also highlight new treatment approaches based on the latest clinical and experimental research.

Serum Osteoprotegerin and Carotid Intima-Media Thickness Are Related to High Arterial Stiffness in Heart Failure with Reduced Ejection Fraction.

Arterial stiffness (AS) is a complex vascular phenomenon with consequences for central hemodynamics and left-ventricular performance. Circulating biomarkers have been associated with AS; however, their value in heart failure is poorly characterized. Our aim was to evaluate the clinical and biomarker correlates of AS in the setting of heart failure with reduced ejection fraction (HFrEF). In 78 hospitalized, hemodynamically stable patients (20 women, 58 men, mean age 65.8 ± 1.41 years) with HFrEF, AS was measured using aortic pulse wave velocity (PWV). Serum OPG, RANKL, sclerostin, and DKK-1 were determined, and the relationships between the clinical variables, vascular-calcification-related biomarkers, and PWV were evaluated by correlation analysis and linear and logistic regression models. OPG and the OPG/RANKL ratio were significantly higher in the group of patients (n = 37, 47.4%) with increased PWV (>10 m/s). PWV was positively correlated with age, left-ventricular ejection fraction, and carotid intima-media thickness (cIMT), and negatively correlated with the glomerular filtration rate. OPG and cIMT were significantly associated with PWV in the logistic regression models when adjusted for hypertension, EF, and the presence of atherosclerotic manifestations. Elevated serum OPG, together with cIMT, were significantly related to increased AS in the setting of HFrEF.

Recent Advances in the Synthesis of ß-Carboline Alkaloids.

ß-Carboline alkaloids are a remarkable family of natural and synthetic indole-containing heterocyclic compounds and they are widely distributed in nature. Recently, these alkaloids have been in the focus of interest, thanks to their diverse biological activities. Their pharmacological activity makes them desirable as sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic or antimicrobial drug candidates. The growing potential inherent in them encourages many researchers to address the challenges of the synthesis of natural products containing complex ß-carboline frameworks. In this review, we describe the recent developments in the synthesis of ß-carboline alkaloids and closely related derivatives through selected examples from the last 5 years. The focus is on the key steps with improved procedures and synthetic approaches. Furthermore the pharmacological potential of the alkaloids is also highlighted.

First total synthesis of ß-carboline alkaloid trigonostemine G and its derivatives.

The ß-carboline core is the base structure of several biologically active natural and unnatural compounds. Herein, we report the first total synthesis of trigonostemine G, which is a newly isolated natural ß-carboline alkaloid from the twigs of Trigonostemon filipes. Synthesis of two structurally close derivatives of trigonostemine G is also reported. Key step of the syntheses involves a nucleophilic addition of 5-{[tert-butyl(dimethyl) silyl]oxy}-1H-indole to 1-formyl-ß-carboline building blocks.

Synthesis and characterization of new fluorescent boro-ß-carboline dyes.

The first representatives of the new fluorescent boro-ß-carboline family were synthesized by the insertion of the difluoroboranyl group into the oxaza or diaza core. The resulting compounds showed good photophysical properties with fine Stokes-shifts in the range of 38-85 nm with blue and green emission. The energetics of the excitation states and molecular orbitals of two members were investigated by quantum chemical computations suggesting effects for the improved properties of diazaborinino-carbolines over oxazaborolo-carbolines. These properties nominated this chemotype as a new fluorophore for the development of fluorescent probes. As an example, diazaborinino-carbolines were used for the specific labeling of anti-Her2 antibody trastuzumab. The fluorescent conjugate showed a high fluorophore-antibody ratio and was confirmed as a useful tool for labeling and confocal microscopy imaging of tumour cells in vitro together with the ex vivo two-photon microscopy imaging of tumour slices.

Synthesis of Indolo[2,3-c]quinolin-6(7H)-ones and Antimalarial Isoneocryptolepine. Computational Study on the Pd-Catalyzed Intramolecular C-H Arylation.

The synthesis of variously substituted indolo[2,3-c]quinolin-6(7H)-ones was developed via Pd-catalyzed intramolecular C-H arylation. This method highlights a strategy for preparing indoloquinoline precursors bearing versatile functional groups and provides a new approach for the synthesis of antimalarial isoneocryptolepine analogues. The plausible ring closure mechanism was examined with quantum chemical calculations, where a trigonal bipyramidal concerted metalation-deprotonation transition state is presumable.

Universal characteristics of particle shape evolution by bed-load chipping.

River currents, wind, and waves drive bed-load transport, in which sediment particles collide with each other and Earth's surface. A generic consequence is impact attrition and rounding of particles as a result of chipping, often referred to in geological literature as abrasion. Recent studies have shown that the rounding of river pebbles can be modeled as diffusion of surface curvature, indicating that geometric aspects of impact attrition are insensitive to details of collisions and material properties. We present data from fluvial, aeolian, and coastal environments and laboratory experiments that suggest a common relation between circularity and mass attrition for particles transported as bed load. Theory and simulations demonstrate that universal characteristics of shape evolution arise because of three constraints: (i) Initial particles are mildly elongated fragments, (ii) particles collide with similarly-sized particles or the bed, and (iii) collision energy is small enough that chipping dominates over fragmentation but large enough that sliding friction is negligible. We show that bed-load transport selects these constraints, providing the foundation to estimate a particle's attrition rate from its shape alone in most sedimentary environments. These findings may be used to determine the contribution of attrition to downstream fining in rivers and deserts and to infer transport conditions using only images of sediment grains.

Reconstructing the transport history of pebbles on Mars.

The discovery of remarkably rounded pebbles by the rover Curiosity, within an exhumed alluvial fan complex in Gale Crater, presents some of the most compelling evidence yet for sustained fluvial activity on Mars. While rounding is known to result from abrasion by inter-particle collisions, geologic interpretations of sediment shape have been qualitative. Here we show how quantitative information on the transport distance of river pebbles can be extracted from their shape alone, using a combination of theory, laboratory experiments and terrestrial field data. We determine that the Martian basalt pebbles have been carried tens of kilometres from their source, by bed-load transport on an alluvial fan. In contrast, angular clasts strewn about the surface of the Curiosity traverse are indicative of later emplacement by rock fragmentation processes. The proposed method for decoding transport history from particle shape provides a new tool for terrestrial and planetary sedimentology.

Universality of fragment shapes.

The shape of fragments generated by the breakup of solids is central to a wide variety of problems ranging from the geomorphic evolution of boulders to the accumulation of space debris orbiting Earth. Although the statistics of the mass of fragments has been found to show a universal scaling behavior, the comprehensive characterization of fragment shapes still remained a fundamental challenge. We performed a thorough experimental study of the problem fragmenting various types of materials by slowly proceeding weathering and by rapid breakup due to explosion and hammering. We demonstrate that the shape of fragments obeys an astonishing universality having the same generic evolution with the fragment size irrespective of materials details and loading conditions. There exists a cutoff size below which fragments have an isotropic shape, however, as the size increases an exponential convergence is obtained to a unique elongated form. We show that a discrete stochastic model of fragmentation reproduces both the size and shape of fragments tuning only a single parameter which strengthens the general validity of the scaling laws. The dependence of the probability of the crack plan orientation on the linear extension of fragments proved to be essential for the shape selection mechanism.

Strong HIV and hepatitis disclosure norms and frequent risk behaviors among Hungarian drug injectors.

Ethnographic interviews and focus groups were conducted between May 2003 and January 2004 among injection drug users (IDUs; n=29) in Budapest, Hungary, to assess knowledge related to HIV, hepatitis B (HBV), and hepatitis C (HCV) and norms, attitudes, and behaviors. Participants perceived themselves at low risk for infection with HIV but at high risk for hepatitis through injection but not sexual exposure. They reported strong disclosure norms for HIV and hepatitis infections, while sexual and injection risk behaviors were influenced by trust about partners' self-report of infection status. Injection networks were small, with infrequent syringe sharing among a few close friends. Cookers and drug filters often were shared, and filters were reused as a backup drug supply. Most sexual relationships were monogamous, and condoms were used rarely. Although participant norms supported HIV/HBV/HCV testing, the lack of available behaviors with injection and sex partners who are close friends. Network interventions among IDUs in Hungary should build on disclosure norms and trust to reduce injection and sex risk. Testing services should be expanded and access increased so that IDUs can act on and reinforce their norms for testing.