Myocardial strain assessment in the human fetus by cardiac MRI using Doppler ultrasound gating and feature tracking.

OBJECTIVES: Assessment of myocardial strain by feature tracking magnetic resonance imaging (FT-MRI) in human fetuses with and without congenital heart disease (CHD) using cardiac Doppler ultrasound (DUS) gating. METHODS: A total of 43 human fetuses (gestational age 28-41 weeks) underwent dynamic cardiac MRI at 3 T. Cine balanced steady-state free-precession imaging was performed using fetal cardiac DUS gating. FT-MRI was analyzed using dedicated post-processing software. Endo- and epicardial contours were manually delineated from fetal cardiac 4-chamber views, followed by automated propagation to calculate global longitudinal strain (GLS) of the left (LV) and right ventricle (RV), LV radial strain, and LV strain rate. RESULTS: Strain assessment was successful in 38/43 fetuses (88%); 23 of them had postnatally confirmed diagnosis of CHD (e.g., coarctation, transposition of great arteries) and 15 were heart healthy. Five fetuses were excluded due to reduced image quality. In fetuses with CHD compared to healthy controls, median LV GLS (- 13.2% vs. - 18.9%; p < 0.007), RV GLS (- 7.9% vs. - 16.2%; p < 0.006), and LV strain rate (1.4 s-1 vs. 1.6 s-1; p < 0.003) were significantly higher (i.e., less negative). LV radial strain was without a statistically significant difference (20.7% vs. 22.6%; p = 0.1). Bivariate discriminant analysis for LV GLS and RV GLS revealed a sensitivity of 67% and specificity of 93% to differentiate between fetuses with CHD and healthy fetuses. CONCLUSION: Myocardial strain was successfully assessed in the human fetus, performing dynamic fetal cardiac MRI with DUS gating. Our study indicates that strain parameters may allow for differentiation between fetuses with and without CHD. CLINICAL RELEVANCE STATEMENT: Myocardial strain analysis by cardiac MRI with Doppler ultrasound gating and feature tracking may provide a new diagnostic approach for evaluation of fetal cardiac function in congenital heart disease. KEY POINTS: • MRI myocardial strain analysis has not been performed in human fetuses so far. • Myocardial strain was assessed in human fetuses using cardiac MRI with Doppler ultrasound gating. • MRI myocardial strain may provide a new diagnostic approach to evaluate fetal cardiac function.

Dynamic Kinetic Resolution of Alcohols by Enantioselective Silylation Enabled by Two Orthogonal Transition-Metal Catalysts.

A nonenzymatic dynamic kinetic resolution of acyclic and cyclic benzylic alcohols is reported. The approach merges rapid transition-metal-catalyzed alcohol racemization and enantioselective Cu-H-catalyzed dehydrogenative Si-O coupling of alcohols and hydrosilanes. The catalytic processes are orthogonal, and the racemization catalyst does not promote any background reactions such as the racemization of the silyl ether and its unselective formation. Often-used ruthenium half-sandwich complexes are not suitable but a bifunctional ruthenium pincer complex perfectly fulfills this purpose. By this, enantioselective silylation of racemic alcohol mixtures is achieved in high yields and with good levels of enantioselection.

Potent inhibition of human carbonyl reductase 1 (CBR1) by the prenylated chalconoid xanthohumol and its related prenylflavonoids isoxanthohumol and 8-prenylnaringenin.

In terms of drug disposal and metabolism SDR21C1 (carbonyl reductase 1; CBR1) exerts an assorted substrate spectrum among a large variety of clinically relevant substances. Additionally, this short-chain dehydrogenase/reductase is extensively expressed in most tissues of the human body, thus underpinning its role in xenobiotic metabolism. Reduction of the chemotherapeutic daunorubicin (DAUN) to daunorubicinol (DAUNol) is a prominent example of its metabolic properties in terms of chemoresistance and cardiotoxicity. The hop-derived prenylated chalcone xanthohumol (XN) and its physiological metabolites isoxanthohumol (IX) and 8-prenylnaringenin (8-PN) have previously been reported to inhibit other DAUN reducing reductases and dehydrogenases including AKR1B1 and AKR1B10. Also with regard to their effects by means of interacting with cancer-related molecular pathways, XN and related prenylated flavonoids in particular have been in the focus of recent studies. In this study, inhibitory properties of these substances were examined with CBR1-mediated 2,3-hexanedione and DAUN reduction. All substances tested in this study turned out to efficiently inhibit recombinant human CBR1 within a low micromolar to submicromolar range. Among the substances tested, 8-PN turned out to be the most effective inhibitor when using 2,3-hexanedione as a substrate (Ki(app) = 180 ±â€¯20 nM). Inhibition rates of recombinant CBR1-mediated DAUN reduction were somewhat weaker with IC50-values ranging from 11 to 20 µM. XN, IX and 8-PN also efficiently inhibited DAUN reduction by SW480 colon adenocarcinoma cytosol (IC50 = 3.71 ±â€¯0.26 µM with 8-PN as inhibitor). This study identifies prenylated inhibitors, which might potentially interact with endogenous CBR1-driven (de-)toxication systems.

Making the Silylation of Alcohols Chiral: Asymmetric Protection of Hydroxy Groups.

The non-enzymatic kinetic resolution of racemic mixtures of alcohols by silylation had been unknown before the turn of the century. This stands in stark contrast to established acylation techniques. The same applies to the related desymmetrization of diols. This might come as a surprise, given the significance of silyl ethers as protecting groups in multistep synthesis of complex molecules. The situation changed after a seminal report by Ishikawa nearly twenty years ago. Since then, enantioselective silylation of alcohols has matured and grown into an independent research field with organocatalytic and transition-metal-catalyzed approaches providing powerful solutions. This Minireview summarizes these recent advances with particular emphasis on the stereoselective dehydrogenative coupling of alcohols and hydrosilanes.

Kinetic Resolution of Tertiary Propargylic Alcohols by Enantioselective Cu-H-Catalyzed Si-O Coupling.

A broad range of tertiary propargylic alcohols were kinetically resolved by catalyst-controlled enantioselective silylation. This non-enzymatic kinetic resolution is catalyzed by a Cu-H species and makes use of the commercially available precatalyst MesCu/(R,R)-Ph-BPE and a simple hydrosilane as the resolving reagent. Both alkyl,aryl- as well as dialkyl-substituted propargylic alcohols participate, and especially high selectivity factors are achieved when the alkyne terminus carries a TIPS group, which also enables facile post-functionalization in this position (s up to 207).

Selective Inhibition of Human AKR1B10 by n-Humulone, Adhumulone and Cohumulone Isolated from Humulus lupulus Extract.

Hop-derived compounds have been subjected to numerous biomedical studies investigating their impact on a wide range of pathologies. Isomerised bitter acids (isoadhumulone, isocohumulone and isohumulone) from hops, used in the brewing process of beer, are known to inhibit members of the aldo-keto-reductase superfamily. Aldo-keto-reductase 1B10 (AKR1B10) is upregulated in various types of cancer and has been reported to promote carcinogenesis. Inhibition of AKR1B10 appears to be an attractive means to specifically treat RAS-dependent malignancies. However, the closely related reductases AKR1A1 and AKR1B1, which fulfil important roles in the detoxification of endogenous and xenobiotic carbonyl compounds oftentimes crossreact with inhibitors designed to target AKR1B10. Accordingly, there is an ongoing search for selective AKR1B10 inhibitors that do not interact with endogeneous AKR1A1 and AKR1B1-driven detoxification systems. In this study, unisomerised α-acids (adhumulone, cohumulone and n-humulone) were separated and tested for their inhibitory potential on AKR1A1, AKR1B1 and AKR1B10. Also AKR1B10-mediated farnesal reduction was effectively inhibited by α-acid congeners with Ki-values ranging from 16.79 ± 1.33 µM (adhumulone) to 3.94 ± 0.33 µM (n-humulone). Overall, α-acids showed a strong inhibition with selectivity (115⁻137 fold) for AKR1B10. The results presented herein characterise hop-derived α-acids as a promising basis for the development of novel and selective AKR1B10-inhibitors.

The hop-derived compounds xanthohumol, isoxanthohumol and 8-prenylnaringenin are tight-binding inhibitors of human aldo-keto reductases 1B1 and 1B10.

Xanthohumol (XN), a prenylated chalcone unique to hops (Humulus lupulus) and two derived prenylflavanones, isoxanthohumol (IX) and 8-prenylnaringenin (8-PN) gained increasing attention as potential anti-diabetic and cancer preventive compounds. Two enzymes of the aldo-keto reductase (AKR) superfamily are notable pharmacological targets in cancer therapy (AKR1B10) and in the treatment of diabetic complications (AKR1B1). Our results show that XN, IX and 8-PN are potent uncompetitive, tight-binding inhibitors of human aldose reductase AKR1B1 (Ki = 15.08 µM, 0.34 µM, 0.71 µM) and of human AKR1B10 (Ki = 20.11 µM, 2.25 µM, 1.95 µM). The activity of the related enzyme AKR1A1 was left unaffected by all three compounds. This is the first time these three substances have been tested on AKRs. The results of this study may provide a basis for further quantitative structure?activity relationship models and promising scaffolds for future anti-diabetic or carcinopreventive drugs.

Inhibition of human anthracycline reductases by emodin - A possible remedy for anthracycline resistance.

The clinical application of anthracyclines, like daunorubicin and doxorubicin, is limited by two factors: dose-related cardiotoxicity and drug resistance. Both have been linked to reductive metabolism of the parent drug to their metabolites daunorubicinol and doxorubicinol, respectively. These metabolites show significantly less anti-neoplastic properties as their parent drugs and accumulate in cardiac tissue leading to chronic cardiotoxicity. Therefore, we aimed to identify novel and potent natural inhibitors for anthracycline reductases, which enhance the anticancer effect of anthracyclines by preventing the development of anthracycline resistance. Human enzymes responsible for the reductive metabolism of daunorubicin were tested for their sensitivity towards anthrachinones, in particular emodin and anthraflavic acid. Intense inhibition kinetic data for the most effective daunorubicin reductases, including IC50- and Ki-values, the mode of inhibition, as well as molecular docking, were compiled. Subsequently, a cytotoxicity profile and the ability of emodin to reverse daunorubicin resistance were determined using multiresistant A549 lung cancer and HepG2 liver cancer cells. Emodin potently inhibited the four main human daunorubicin reductases in vitro. Further, we could demonstrate that emodin is able to synergistically sensitize human cancer cells towards daunorubicin at clinically relevant concentrations. Therefore, emodin may yield the potential to enhance the therapeutic effectiveness of anthracyclines by preventing anthracycline resistance via inhibition of the anthracycline reductases. In symphony with its known pharmacological properties, emodin might be a compound of particular interest in the management of anthracycline chemotherapy efficacy and their adverse effects.