Repaglinide-Solid Lipid Nanoparticles in Chitosan Patches for Transdermal Application: Box-Behnken Design, Characterization, and In Vivo Evaluation.

Background: Repaglinide (REP) is an antidiabetic drug with limited oral bioavailability attributable to its low solubility and considerable first-pass hepatic breakdown. This study aimed to develop a biodegradable chitosan-based system loaded with REP-solid lipid nanoparticles (REP-SLNs) for controlled release and bioavailability enhancement via transdermal delivery. Methods: REP-SLNs were fabricated by ultrasonic hot-melt emulsification. A Box-Behnken design (BBD) was employed to explore and optimize the impacts of processing variables (lipid content, surfactant concentration, and sonication amplitude) on particle size (PS), and entrapment efficiency (EE). The optimized REP-SLN formulation was then incorporated within a chitosan solution to develop a transdermal delivery system (REP-SLN-TDDS) and evaluated for physicochemical properties, drug release, and ex vivo permeation profiles. Pharmacokinetic and pharmacodynamic characteristics were assessed using experimental rats. Results: The optimized REP-SLNs had a PS of 249±9.8 nm and EE of 78%±2.3%. The developed REP-SLN-TDDS demonstrated acceptable characteristics without significant aggregation of REP-SLNs throughout the casting and drying processes. The REP-SLN-TDDS exhibited a biphasic release pattern, where around 36% of the drug load was released during the first 2 h, then the drug release was sustained at around 80% at 24 h. The computed flux across rat skin for the REP-SLN-TDDS was 2.481±0.22 µg/cm2/h in comparison to 0.696±0.07 µg/cm2/h for the unprocessed REP, with an enhancement ratio of 3.56. The REP-SLN-TDDS was capable of sustaining greater REP plasma levels over a 24 h period (p<0.05). The REP-SLN-TDDS also reduced blood glucose levels compared to unprocessed REP and commercial tablets (p<0.05) in experimental rats. Conclusion: Our REP-SLN-TDDS can be considered an efficient therapeutic option for REP administration.

Genome sequencing of Enterococcus faecium NT04, an oral microbiota revealed the production of enterocin A/B active against oral pathogens.

Objective: This study aimed to isolate and investigate a bacterium from an Egyptian adult's healthy oral cavity, focusing on its probiotic properties, especially its antagonistic activity against oral pathogens. Methods: The isolated bacterium NT04 using 16S rRNA gene sequencing, was identified as Enterococcus faecium. In this study, the whole genome of Enterococcus faecium NT04 was sequenced and annotated by bioinformatics analysis tools. Results: Numerous genes encoding the production of diverse metabolic and probiotic properties, such as bacteriocin-like inhibitory substances (Enterocin A and B), cofactors, antioxidants, and vitamins, were confirmed by genomic analysis. There were no pathogenicity islands or plasmid insertions found. This strain is virulent for host colonization rather than invasion. Conclusion: Genomic characteristics of strain NT04 support its potentiality as an anti-oral pathogen probiotic candidate.

The mitigating effect of Spirulina (Arthrospira platensis) on the hemotoxicity of gibberellic acid on juvenile tilapia (Oreochromis niloticus).

The use of plant growth regulators has led to environmental contamination of water bodies that occur adjacent to agricultural areas. Some of these chemicals are bioactive, not only to plants, but also to non-target exposed biota, namely of the aquatic compartment. Previous work demonstrated the establishment of hepato- and nephrotoxic effects in juvenile tilapia (Oreochromis niloticus) exposed via aquatic media to gibberellic acid (GA3), which is among the most used plant growth regulators, in agricultural practices. Here, we investigated the effect of GA3 on hematological indices, poikilocytosis, nuclear abnormalities, and genotoxic indices measured in Nile tilapia (Oreochromis niloticus), as well as the putative protective effects of dietary supplementation of Spirulina (Arthrospira platensis). Fish were evenly assorted into 5 groups: group I served as a control, and groups II-V were fed diets supplemented with Spirulina at rates of 0 g/kg, 5 g/kg, 20 g/kg, and 100 g/kg, respectively, for 2 months before being exposed to 150 mg/L GA3. The results revealed that GA3 exposure decreased significantly all hematological indices (P < 0.05), except leucocytes and mean corpuscular hemoglobin concentration (MCHC), compared to the control group (P > 0.05). GA3 exposure increased significantly the percentage of nuclear abnormalities, altered erythrocytes and the percentages of tail DNA, compared to the control group (P < 0.05). Spirulina supplementation restored the hematological, poikilocytosis, nuclear abnormalities, and the percentages of tail DNA to near normal levels. The 100 g/kg SP treatment was the most effective in attaining such effect, showing concentration-dependency. The present study reinforces our findings of the toxicity of GA3 on O. niloticus and suggests that the addition of Spirulina to fish diet can mitigate the hemotoxic effects of GA3.

Design, Synthesis, Molecular Docking Study and Anti-Hepatocellular Carcinoma Evaluation of New Bis-Triazolothiadiazines.

OBJECTIVE: The reaction of bis(4-amino-4H-1,2,4-triazole-3-thiol) with hydrazonoyl halides and α-halo-ketones gave a new series of bis-1,2,4-triazolo[3,4-b]thiadiazine derivatives. METHODS: The structure of the new products was established on the basis of their elemental and spectral data (mass, 1H NMR, 13C NMR and IR) and an alternate method. RESULTS: Several of the synthesized products were subjected to in vitro anticancer screening against human hepatocellular carcinoma (HepG-2) and the results showed that compounds 16, 14 and 12 have promising activities (IC50 value of 24.8±9.1, 28.3±0.5, and 31±2.9µM, respectively) compared with Harmine reference drug (IC50 value of 22.4±1.11 µM). CONCLUSION: Moreover, molecular docking studies were performed to analyze the binding modes of the discovered hits into the active site of DYRK1A using iGEMDOCK.

Facile synthesis and antiproliferative activity of new 3-cyanopyridines.

BACKGROUND: Pyridines have been reported to possess various pharmacological activities. RESULTS: Sodium 3-oxo-3-(2-oxo-2H-chromen-3-yl)prop-1-en-1-olate (2) and sodium 3-oxo-3-(3-oxo-3H-benzo[f]chromen-2-yl)prop-1-en-1-olate (7) were prepared and reacted with 2-cyano-N'-(1-aryl(heteryl)ethylidene)acetohydrazides 3a-d to produce 2-oxo-1,2-dihydropyridine-3-carbonitrile derivatives 5a-d and 9a-d, respectively, in good yields. Also, 3a-d reacted with sodium (2-oxocyclopentylidene)methanolate (11a) or sodium (2-oxocyclohexylidene) methanolate (11b) to yield 2-oxo-tetrahydro-1H-cyclopenta[b]pyridine-3-carbonitriles 13a-d and 2-oxo-hexahydroquinoline-3-carbonitriles 13e-h, respectively. The mechanisms that account for the formation of the products are discussed. Additionally, the structures of all the newly synthesized products are confirmed, based on elemental analysis and spectral data. Several of the newly synthesized compounds are evaluated for their antitumor activity against HEPG2 and their structure activity relationship (SAR) was studied. CONCLUSIONS: The results revealed that the pyridine derivatives 5c and 5d (IC50 = 1.46, 7.08 µM, respectively) have promising antitumor activity against liver carcinoma cell line (HEPG2), compared to the reference drug, doxorubicin.