Design, synthesis and molecular docking study of new pyrimidine-based hydrazones with selective anti-proliferative activity against MCF-7 and MDA-MB-231 human breast cancer cell lines.

Efforts were directed on the design, synthesis and evaluation of the anticancer activity of some pyrimidine-based hydrazones against two breast cancer cell lines, MCF-7 and MDA-MB-231. Preliminary screening results revealed that some candidates scrutinized for their antiproliferative activities exhibited IC50 values of 0.87 µM-12.91 µM in MCF-7 and 1.75 µM-9.46 µM in MDA-MB-231 cells, indicating almost equal activities on both cell lines and better growth inhibition activities than those of the positive control 5-fluorouracil (5-FU) which displayed IC50 values of 17.02 µM and 11.73 µM respectively. Selectivity of the significantly active compounds was estimated against MCF-10A normal breast cells when compounds 7c, 8b, 9a and 10b exhibited superior activity for cancerous cells than for normal cells when compound 10b presented the best selectivity Index (SI) with respect to both MCF-7 and MDA-MB-231 cancer cells in comparison to the reference drug 5-FU. Mechanisms of their actions were explored by inspecting activation of caspase-9, annexin V staining and cell cycle analysis. It was noticed that compounds 7c, 8b, 8c 9a-c and 10b produced an increase in caspase-9 levels in MCF-7 treated cells with 10b inducing the highest elevation (27.13 ± 0.54 ng/mL) attaining 8.26-fold when compared to control MCF-7 which was higher than that of staurosporine (19.011 ± 0.40 ng/mL). The same compounds boosted caspase-9 levels in MDA-MB-231 treated cells when an increase in caspase-9 concentration reaching 20.40 ± 0.46 ng/mL (4.11-fold increase) was observed for compound 9a. We also investigated the role of these compounds for their increasing apoptosis ability against the 2 cell lines. Compounds 7c, 8b and 10b tested on MCF-7 cells displayed pre-G1 apoptosis and arrested cell cycle in particular at the S and G1 phases. Further clarification of their effects was made by modulating their related activities as inhibitors of ARO and EGFR enzymes when 8c and 9b showed 52.4% and 58.9% inhibition activity relative to letrozole respectively and 9b and 10b showed 36% and 39% inhibition activity of erlotinib. Also, the inhibition activity was verified by docking into the chosen enzymes.

Dual-effects of caffeinated hyalurosomes as a nano-cosmeceutical gel counteracting UV-induced skin ageing.

Caffeine (CAF) is a challenging natural bioactive compound with proven antiaging efficacy. However, being hydrophilic hampers its permeation through the skin. Our aim is to develop a novel CAF-loaded nano-cosmeceutical tool counteracting skin photoaging via improving CAF skin permeation using a bioactive nanocarrier. Caffeinated hyalurosomes are novel biocompatible antiaging nanoplatforms designed by immobilization of phospholipid vesicles with a hyaluronan polymer. Physicochemical properties of the selected hyalurosomes formulation showed nano-sized vesicles (210.10 ± 1.87 nm), with high zeta potential (-31.30 ± 1.19 mv), and high encapsulation efficiency (84.60 ± 1.05%). In vitro release results showed outstanding sustained release profile from caffeinated hyalurosomes compared to the CAF-loaded in conventional gel over 24 h. The in-vivo study revealed a photoprotective effect of caffeinated hyalurosomes, reflected from the intact and wrinkling-free skin. Results of biochemical analyses of oxidative stress, pro-inflammatory mediators, and anti-wrinkling markers further confirmed the efficacy of the prepared hyalurosomes compared to the CAF conventional gel. Finally, histopathological examination demonstrated normal histological structures of epidermal layers with minimal inflammatory cell infiltrates in the caffeinated hyalurosomes group compared to the positive control group. Conclusively, caffeinated hyalurosomes successfully achieved enhanced CAF loading and penetration into the skin besides the hydration effect of hyaluronan. Consequently, the developed delivery system presents a promising skin protection nano-platforms via the double effects of both hyaluronan and CAF, hence it guards against skin photodamage.

Neuroprotective Effect of Artichoke-Based Nanoformulation in Sporadic Alzheimer's Disease Mouse Model: Focus on Antioxidant, Anti-Inflammatory, and Amyloidogenic Pathways.

The vast socio-economic impact of Alzheimer's disease (AD) has prompted the search for new neuroprotective agents with good tolerability and safety profile. With its outstanding role as antioxidant and anti-inflammatory, alongside its anti-acetylcholinesterase activity, the artichoke can be implemented in a multi-targeted approach in AD therapy. Moreover, artichoke agricultural wastes can represent according to the current United Nations Sustainable Development goals an opportunity to produce medicinally valuable phenolic-rich extracts. In this context, the UPLC-ESI-MS/MS phytochemical characterization of artichoke bracts extract revealed the presence of mono- and di-caffeoylquinic acids and apigenin, luteolin, and kaempferol O-glycosides with remarkable total phenolics and flavonoids contents. A broad antioxidant spectrum was established in vitro. Artichoke-loaded, chitosan-coated, solid lipid nanoparticles (SLNs) were prepared and characterized for their size, zeta potential, morphology, entrapment efficiency, release, and ex vivo permeation and showed suitable colloidal characteristics, a controlled release profile, and promising ex vivo permeation, indicating possibly better physicochemical and biopharmaceutical parameters than free artichoke extract. The anti-Alzheimer potential of the extract and prepared SLNs was assessed in vivo in streptozotocin-induced sporadic Alzheimer mice. A great improvement in cognitive functions and spatial memory recovery, in addition to a marked reduction of the inflammatory biomarker TNF-α, ß-amyloid, and tau protein levels, were observed. Significant neuroprotective efficacy in dentate Gyrus sub-regions was achieved in mice treated with free artichoke extract and to a significantly higher extent with artichoke-loaded SLNs. The results clarify the strong potential of artichoke bracts extract as a botanical anti-AD drug and will contribute to altering the future medicinal outlook of artichoke bracts previously regarded as agro-industrial waste.

Novel Siprulina platensis Bilosomes for Combating UVB Induced Skin Damage.

The recent interest in bioactive compounds from natural sources has led to the evolution of the skin care industry. Efforts to develop biologically active ingredients from natural sources have resulted in the emergence of enhanced skin care products. Spirulina (SPR), a nutritionally enriched cyanobacteria-type microalga, is rich in nutrients and phytochemicals. SPR possesses antioxidant, immunomodulatory, and anti-inflammatory activities. Spirulina-loaded bilosomes (SPR-BS), a novel antiaging drug delivery system, were designed for the first time by incorporation in a lecithin−bile salt-integrated system for bypassing skin delivery obstacles. The optimized BS had good entrapment efficiency, small particle size, optimal zeta potential, and sustained drug release pattern. Blank and SPR-loaded BS formulations were safe, with a primary irritancy index of <2 based on the Draize test. In vivo tests were conducted, and photoprotective antiaging effects were evaluated visually and biochemically by analyzing antioxidant, anti-inflammatory, and anti-wrinkling markers following ultraviolet (UV) B irradiation. Results of biochemical marker analysis and histopathological examination confirmed the superior antiaging effect of SPR-BS compared with SPR. Thus, SPR-loaded BS is a promising nanoplatform for SPR delivery, can be used for treating UV-induced skin damage, and offers maximum therapeutic outcomes.

Combinatorial strategy of epigenetic and hormonal therapies: A novel promising approach for treating advanced prostate cancer.

AIMS: Estrogens act as key factors in prostate biology, cellular proliferation and differentiation as well as cancer development and progression. The expression of estrogen receptor (ER)-ß appears to be lost during prostate cancer progression through hypermethylation mechanism. Epigenetic drugs such as 5-aza-2'-deoxycytidine (5-AZAC) and Trichostatin A (TSA) showed efficacy in restoring ERß expression in prostate cancer cells. This study was designed to explore the potential anti-carcinogenic effects resulting from re-expressing ERß1 using 5-AZAC and/or TSA, followed by its stimulation with Diarylpropionitrile (DPN), a selective ERß1 agonist, in prostate cancer cell line PC-3. MAIN METHODS: Cells were treated with 5-AZAC, TSA, DPN and their combination. Subsequently, they were subjected to proliferation assays, determinations of ERß1 expression, protein levels of active caspase-3, cyclin D1, ß-catenin and VEGF. KEY FINDINGS: Treatment with these drugs exhibited an increase in ERß1 expression to different extents as well as active caspase-3 levels. Meanwhile, a significant reduction in cyclin D1, VEGF and ß-catenin levels was achieved as compared to the vehicle control group (p < 0.05). Interestingly, the triple combination regimen led to the most prominent anti-tumor responses in terms of increased apoptosis, reduced proliferation as well as angiogenesis. SIGNIFICANCE: The results support the notion that ERß1 acts as a tumor suppressor protein and suggest that sequential ERß1 expression and activation can offer significant anti-tumor responses. The study highlights that the strategy of merging epigenetic and hormonal therapies may be beneficial in treating advanced prostate cancer.