Progressive lung fibrosis is associated with poorly understood aging-related endothelial cell dysfunction. To gain insight into endothelial cell alterations in lung fibrosis we performed single cell RNA-sequencing of bleomycin-injured lungs from young and aged mice. Analysis reveals activated cell states enriched for hypoxia, glycolysis and YAP/TAZ activity in ACKR1+ venous and TrkB+ capillary endothelial cells. Endothelial cell activation is prevalent in lungs of aged mice and can also be detected in human fibrotic lungs. Longitudinal single cell RNA-sequencing combined with lineage tracing demonstrate that endothelial activation resolves in young mouse lungs but persists in aged ones, indicating a failure of the aged vasculature to return to quiescence. Genes associated with activated lung endothelial cells states in vivo can be induced in vitro by activating YAP/TAZ. YAP/TAZ also cooperate with BDNF, a TrkB ligand that is reduced in fibrotic lungs, to promote capillary morphogenesis. These findings offer insights into aging-related lung endothelial cell dysfunction that may contribute to defective lung injury repair and persistent fibrosis.

Understanding the dynamic pathogenesis and treatment response in pulmonary diseases requires probing the lung at cellular resolution in real time. Despite advances in intravital imaging, optical imaging of the lung during active respiration and circulation has remained challenging. Here, we introduce the crystal ribcage: a transparent ribcage that allows multiscale optical imaging of the functioning lung from whole-organ to single-cell level. It enables the modulation of lung biophysics and immunity through intravascular, intrapulmonary, intraparenchymal and optogenetic interventions, and it preserves the three-dimensional architecture, air–liquid interface, cellular diversity and respiratory–circulatory functions of the lung. Utilizing these capabilities on murine models of pulmonary pathologies we probed remodeling of respiratory–circulatory functions at the single-alveolus and capillary levels during disease progression. The crystal ribcage and its broad applications presented here will facilitate further studies of nearly any pulmonary disease as well as lead to the identification of new targets for treatment strategies.

Indole alkaloids, a class of plant-derived nitrogen-containing compounds, have emerged as promising candidates for osteoporosis treatment. Their favorable biocompatibility profile demonstrated efficacy in preclinical models, and low reported toxicity make them attractive alternatives to existing therapies. This review focuses on the therapeutic potential of specific indole alkaloids, including vindoline, rutaecarpine, harmine, and its derivatives, in promoting bone health and managing osteoporosis.

Cyclic-nucleotide phosphodiesterases (PDEs) represent a superfamily of enzymes playing a pivotal role in cell signaling by controlling cAMP and cGMP levels in response to receptor activation. PDE activity and expression are linked to many diseases including inflammatory diseases. In light of their specific biochemical properties, PDE inhibition has attracted the interest of several researrs In this context, PDE4 inhibition induces anti-inflammatory effects. Piclamilast and rolipram, well-known PDE4 inhibitors, are endowed with common side effects. The selective phosphodiesterase 4B (PDE4B) inhibitors could be a promising approach to overcome these side effects. In the present study, six potential PDE4B inhibitors have been investigated. Through this study, we identified three PDE4B inhibitors in human macrophages activated by lipopolysaccharide. Interestingly, two of them reduced reactive oxygen species production in pro-inflammatory macrophages.

A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2–5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure–activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC₅₀ = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC₅₀ = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC₅₀ = 3.3 µM, CC₅₀ = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD_7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH_7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold.

As part of our ongoing attempt to broaden the applications of the amidoxime moiety as a potential source of new antileishmanial agents, this study focuses on the product 4-(5-Benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-2-nitrobenzamide. This unexpected amide was obtained in an 85% yield as the major product with a conventional amidoxime synthesis protocol (Ethanol/Na₂CO₃) involving the reaction of hydroxylamine and a nitrile group. The formation of this amide derivative instead of the expected amidoxime can be attributed to two complementary effects: the strong electron effect of the nitro group and the influence of ethanol, a polar protic solvent. Alternatively, the desired amidoxime derivative, 4-(5-benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-N′-hydroxy-2-nitrobenzimidamide, was obtained in an 80% yield by an alternative protocol (DMSO/KOtBu). This original compound, featuring a nitro group in the ortho position to the amidoxime, will be further evaluated, both in the field of medicinal chemistry and in other relevant areas, highlighting an unusual method to access amidoximes from hindered substrates.

Abstract

Dyrosauridae, a clade of neosuchian crocodyliforms, was a significant component of terrestrial and aquatic ecosystems across the latest Cretaceous to Paleogene of North Africa. Here, we report a dyrosaurid mandibular symphysis recovered from the middle–upper Campanian Quseir Formation near Kharga Oasis in the southern Western Desert of Egypt.

This is a partial mandible (MUVP 635), including dentaries and splenials, assigned to Dyrosauridae based on its dental pattern, size, and the shape of the splenial in the symphysis. MUVP 635 exhibits alveolar diameters shorter than the interalveolar distances within the same row. Moreover, the seventh dentary alveolus is significantly large, comparable in size to the fourth dentary alveolus, while the sixth dentary alveolus is positioned close to the seventh dentary alveolus and is as small as the eighth dentary alveolus, which is adjacent to the ninth dentary alveolus. Phylogenetic analysis places MUVP 635 as an early-diverging member of Dyrosauridae, consistent with its middle–late Campanian age. It aligns with a polytomy with Chenanisuchus lateroculi and Anthracosuchus balrogus identified as the most basal members of Dyrosauridae. The discovery of new dyrosaurid material in the Quseir Formation extends the range of Dyrosauridae to the middle Campanian, highlighting the taxonomic richness of the dyrosaurid clade across North Africa and supporting hypotheses of the African origin for this family.

Simvastatin (SV) is a poorly soluble drug; its oral administration is associated with a significant problem: Myopathy. The present study aims to formulate SV microsponges that have the potential to minimize the myotoxicity accompanying the oral administration of the drug. SV microsponges were prepared by exploiting the emulsion solvent evaporation technique. The % entrapment efficiency (%EE) of the drug approached 82.54 ± 1.27%, the mean particle size of SV microsponges ranged from 53.80 ± 6.35 to 86.03 ± 4.79 µm in diameter, and the % cumulative drug release (%CDR) of SV from microsponges was significantly higher than that from free drug dispersion much more, the specific surface area of the optimized microsponges formulation was found to be 16.6 m²/g revealed the porosity of prepared microsponges. Histological and glycogen histochemical studies in the skeletal muscles of male albino rats revealed that microsponges were safer than free SV in minimizing myotoxicity. These findings were proven by Gene expression of Mitochondrial fusion and fission (Mfn1) & (Fis1) and (Peroxisome proliferator-activated receptor gamma co-activator 1α) PGC-1α. Finally, our study ascertained that SV microsponges significantly decreased the myotoxicity of SV.

In relation to its rapid infrastructure expansion, exemplified by projects like the Najran Valley Dam or the rehabilitation of agricultural terraces, Saudi Arabia stands out among the Arabian Gulf nations. To mitigate the earthquake-related risks effectively, it is imperative to conduct an exhaustive analysis of its natural hazards. The southwesternmost region of Saudi Arabia is the main subject area of this study for the probabilistic seismic hazard assessment (PSHA), which aims to identify the peak ground acceleration (PGA) and spectral acceleration (SA) values. The investigation encompasses a 10% and 5% probability of occurrence over a 50-year exposure time for both B/C and C NEHRP soils. In order to take into account the earthquake activity that takes place in the vicinity of the Red Sea Rift, which in fact may have an impact on the seismic hazard in this active tectonic region, different seismic source zones were especially designed for this evaluation. Various characteristics such as the uncertainties related to the b-value, the expected maximum magnitude, and different ground motion prediction equations (GMPEs) were integrated using a logic tree scheme. Additionally, regression relationships between the computed ground motion values were established, and a novel design response spectrum was developed and recommended for several cities. Regarding the key findings, it is significant to highlight that the seismic hazard decreases towards the northeast, when moving away from the Red Sea Rift, confirming anticipated trends where proximity to the rift corresponds to increased seismic hazard. Notably, cities such as Farasan Island, Jazan, Al Qunfundhah, Al Lith and Al Birk present the highest observed hazard values among all the cities analyzed. For these cities, the obtained maximum SA values for both 475 and 975 years under B/C site conditions are as follows: 0.268 g and 0.412 g, 0.121 g and 0.167 g, 0.099 g and 0.150 g, 0.083 g and 0.135 g, and 0.066 g and 0.118 g, respectively. These results emphasize the crucial necessity of adequately evaluating and thoroughly updating the seismic hazard inherent to these particular areas to enhance the risk reduction and disaster readiness initiatives.