Efficacy of BAY 60-2770, a Soluble Guanylate Cyclase Activator, for Coronary Spasm in Animal Models.

Ischemia with non-obstructive coronary arteries (INOCA), caused by coronary artery spasm, has gained increasing attention owing to the poor quality of life of impacted patients. Therapeutic options to address INOCA remain limited, and developing new therapeutic agents is desirable. Here, we examined whether soluble guanylate cyclase (sGC) activators could be beneficial in preventing coronary spasms. In organ chamber experiments with isolated canine coronary arteries, prostaglandin F2 α -induced, endothelin-1-induced, 5-hydroxytryptamine-induced, and potassium chloride-induced contractions were suppressed by the sGC activator BAY 60-2770 (0.1, 1, and 10 nM). In isolated pig coronary arteries, BAY 60-2770 (0.1, 1, and 10 nM) could prolong the cycle length of phasic contractions induced by 3,4-diaminopyridine, as well as lower the peak and bottom tension of the contraction in a concentration-dependent manner. Additionally, BAY 60-2770 (1 pM-0.1 µM) evoked a concentration-related relaxation to a greater extent in small (first diagonal branch) coronary arteries than in large (left anterior descending) coronary arteries. In vasopressin-induced angina model rats, pretreatment with BAY 60-2770 (3 µg/kg) suppressed electrocardiogram S-wave depression induced by arginine vasopressin without affecting changes in mean blood pressure and heart rate. These findings suggest that BAY 60-2770 could be valuable in preventing both large and small coronary spasms. Therefore, sGC activators could represent a novel and efficacious therapeutic option for INOCA. SIGNIFICANCE STATEMENT: The soluble guanylate cyclase (sGC) activator BAY 60-2770 exerted antispastic effects on the coronary arteries in animal vasospasm models as proof-of-concept studies. These data can help to support potential clinical development with sGC activators, suitable for human use in patients with vasospastic angina.

The link between ancient microbial fluoride resistance mechanisms and bioengineering organofluorine degradation or synthesis.

Fluorinated organic chemicals, such as per- and polyfluorinated alkyl substances (PFAS) and fluorinated pesticides, are both broadly useful and unusually long-lived. To combat problems related to the accumulation of these compounds, microbial PFAS and organofluorine degradation and biosynthesis of less-fluorinated replacement chemicals are under intense study. Both efforts are undermined by the substantial toxicity of fluoride, an anion that powerfully inhibits metabolism. Microorganisms have contended with environmental mineral fluoride over evolutionary time, evolving a suite of detoxification mechanisms. In this perspective, we synthesize emerging ideas on microbial defluorination/fluorination and fluoride resistance mechanisms and identify best approaches for bioengineering new approaches for degrading and making organofluorine compounds.

Synthetic strategy for the production of electrically polarized polyvinylidene fluoride-trifluoroethylene-co-polymer osseo-functionalized with hydroxyapatite scaffold.

The physiological mechanism of bone tissue regeneration is intricately organized and involves several cell types, intracellular, and extracellular molecular signaling networks. To overcome the drawbacks of autografts and allografts, a number of synthetically produced scaffolds have been manufactured by integrating ceramics, polymers, and their hybrid-composites. Considering the fact that natural bone is composed primarily of collagen and hydroxyapatite, ceramic-polymer composite materials seem to be the most viable alternative to bone implants. Here, in this experimental study, copolymer PVDF-TrFE has been amalgamated with HA ceramics to produce composite scaffolds as bone implants. In order to fabricate PVDF-TrFE-HA (polyvinylidene fluoride-trifluoroethylene-hydroxyapatite) composite scaffolds, solvent casting-particulate leaching technique was devised. Two scaffold specimens were produced, with different PVDF-TrFE and HA molar ratios (70:30 and 50:50), and then electrically polarized to observe the subsequent polarization impact on the tissue growth and the suppression of bacterial cell proliferation. Both the specimens underwent characterization to analyze their biocompatibility and bactericidal activities. The bacterial culture of Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) bacteria on the composites was studied to understand the antibacterial characteristics. Moreover, MG63 cells cultured on these as-formed composites provided information about osteogenesis. Improved osteogenesis and antibacterial efficacy were observed on both the composites. However, the composite with 70 wt% PVDF-TrFE and 30 wt% HA showed a higher bactericidal effect as well as osteogenesis. It was found that PVDF-TrFE-HA-based biomaterials have the potential for bone tissue engineering applications.

Discovery of a new 1-(phenylsulfonyl)-1H-indole derivative targeting the EphA2 receptor with antiproliferative activity on U251 glioblastoma cell line.

In our continuing effort devoted at developing agents targeting the EphA2 receptor by means of protein-protein interaction (PPI) inhibitors, we report here the design and synthesis of a new class of l-ß-homotryptophan conjugates of 3-ß-hydroxy-Δ5-cholenic acid bearing a set of arylsulfonyl substituents at the indole nitrogen atom. An extensive structure-activity relationship (SAR) analysis indicates that the presence of a bulky lipophilic moiety at the indole nitrogen is fundamental for improving potency on the EphA2 receptor, while abrogating activity on the EphB1-EphB3 receptor subtypes. A rational exploration, guided by the combined application of an experimental design on σp and π physicochemical descriptors and docking simulations, led to the discovery of UniPR1454, a 1-(4-(trifluoromethyl)phenyl)sulfonyl derivative acting as potent and competitive EphA2 antagonist able to inhibit ephrin-A1 dependent signals and to reduce proliferation of glioblastoma (U251) cell line at micromolar concentration.