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.

Nanoporous aluminum metal–organic framework (Al-MOF) was synthesized via solvothermal methods and employed as a carrier matrix for in vitro drug delivery of Umbelliferon (Um). The encapsulated Um was gradually released over seven days at 37 °C, using simulated body fluid phosphate-buffered saline (PBS) at pH 7.4 as the release medium. The drug release profile suggests the potential of Al-MOF nanoparticles as effective drug delivery carriers. Structural and chemical analyses of Um-loaded Al-MOF nanoparticles (Um-Al MOF) were conducted using Fourier-transform infrared (FTIR) spectroscopy, X-ray diffractometry (XRD), and ultraviolet–visible (UV–Vis) spectroscopy. Thermal gravimetric analysis (TGA) was employed to investigate the thermal stability of the Al-MOF nanoparticles, while Transmission Electron Microscopy (TEM) was utilized to assess their morphological features. Um-Al MOF nanoparticles demonstrated notable antioxidant and anti-inflammatory properties compared to Um and Al-MOF nanoparticles individually. Moreover, they exhibited significant enhancement in wound healing in an earthworm model. These findings underscore the potential of Al-MOF nanoparticles as a promising drug delivery system, necessitating further investigations to explore their clinical applicability.

Background Several studies have been reported previously on the bioactivities of different extracts of marine
molluscs. Therefore, we decided to evaluate the cytotoxic and antimicrobial activities of S. pharaonis ink as a highly
populated species in the Red Sea. We extracted the flavonoids from the ink and analyzed their composition. Then we evaluated systematically the cytotoxic and antimicrobial properties of this extract. A pharmacokinetic study was also conducted using SwissADME to assess the potential of the identified flavonoids and phenolic compounds from the ink extract to be orally active drug candidates.

Results Cytotoxic activity was evaluated against 5 cell lines (MCF7, Hep G2, A549, and Caco2) at different
concentrations (0.4 μg/mL, 1.6 μg/mL, 6.3 μg/mL, 25 μg/mL, 100 μg/mL). The viability of examined cells was reduced by the extract in a concentration-dependent manner. The highest cytotoxic effect of the extract was recorded against A549 and Hep G2 cancer cell lines cells with IC50 = 2.873 and 7.1 μg/mL respectively. The mechanistic analysis by flow cytometry of this extract on cell cycle progression and apoptosis induction indicated that the extract arrests the cell cycle at the S phase in Hep G2 and MCF7, while in A549 cell arrest was recorded at G1 phase. However, it causes G1 and S phase arrest in Caco2 cancer cell line. Our data showed that the extract has significant antimicrobial activity against all tested human microbial pathogens. However, the best inhibitory effect was observed against Candida albicans ATCC 10,221 with a minimum inhibitory concentration (MIC) of 1.95 μg/mL. Pharmacokinetic analysis using Swiss ADME showed that most flavonoids and phenolics compounds have high drug similarity as they satisfy Lipinski’s criteria and have WLOGP values below 5.88 and TPSA below 131.6 Å2.

Conclusion S. pharaonis ink ethanolic extract showed a promising cytotoxic potency against various cell lines and
a remarkable antimicrobial action against different pathogenic microbial strains. S. pharaonis ink is a novel source
of important flavonoids that could be used in the future in different applications as a naturally safe and feasible
alternative of synthetic drugs.

Keywords Flavonoids, Red Sea, Cytotoxicity, Cephalopods, Antimicrobial activity

This study aimed to investigate the histological and histochemical
characterizations of the ink gland of the sea hare “Aplysia argus”.This gland
is composed of two covering epithelium and an inner matrix. The covering
epithelium involved the cubodial facing the mantle cavity and the columnar
facing the mantle shelf. Underneath the covering cuboidal epithelium, there
are bundles of collagenous fibers permeated by two types of granulated
cells. The columnar covering epithelium underlies an adipose connective
tissue that includes dispersed cells between adipocytes. The inner matrix of
the ink gland possesses three types of secretory vesicles; namely, dark-Red,
granulated and transparent. Histochemical investigation indicated that the
granulated cells content included neutral mucopolysaccharides and protein,
while they were devoid of acid mucopolysaccharides. The dark-red vesicles
possess a mixture of acid and neutral mucopolysaccharides; whereas, the
granulated vesicles contain acid mucopolysaccharides only. The dark-red
and granulated vesicles contain protein contents. The histological
characteristics of the ink gland of Aplysia argus corroborated the general
organization of aplysiids. To the best of our knowledge, new data were
added in the current work (for the first time) about the two different types of
granulated cells and adipose connective tissue, in addition to the
investigation of the histochemical contents of granulated cells, secretory
vesicles and dispersed cells.