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Abeer S Hassan,1 Amal Hofni,2 Mohammed AS Abourehab,3 Iman AM Abdel-Rahman4 1Department of Pharmaceutics, Faculty of Pharmacy, South Valley University, Qena, Egypt; 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Minia University, Minia, Egypt; 4Department of Pharmacognosy, Faculty of Pharmacy, South Valley University, Qena, EgyptCorrespondence: Abeer S Hassan, Department of Pharmaceutics, Faculty of Pharmacy, South Valley University, Qena, Egypt, Tel +201012060262, Email abeer.saad@svu.edu.egIntroduction: Ginger extract (GE) has sparked great interest due to its numerous biological benefits. However, it suffers from limited skin permeability, which challenges its transdermal application. The target of the current work was to develop transethosomes as a potential nanovehicle to achieve enhanced transdermal delivery of GE through the skin.Methods: GE–loaded transethosomes were prepared by cold injection using different edge activators. The fabricated nanovesicles were evaluated for particle size, ζ-potential, encapsulation efficiency, and in vitro drug release. The selected formulation was then laden into the hydrogel system and evaluated for ex vivo permeability and in vivo anti-inflammatory activity in a carrageenan-induced rat-paw edema model.Results: The selected formulation comprised of sodium deoxycholate exhibited particle size of 188.3± 7.66 nm, ζ-potential of − 38.6± 0.08 mV, and encapsulation efficiency of 91.0%± 0.24%. The developed transethosomal hydrogel containing hydroxypropyl methylcellulose was homogeneous, pseudoplastic, and demonstrated sustained drug release. Furthermore, it exhibited improved flux (12.61± 0.45 μg.cm2/second), apparent skin permeability (2.43± 0.008× 10− 6 cm/second), and skin deposition compared to free GE hydrogel. In vivo testing and histopathological examination revealed that the GE transethosomal hydrogel exhibited significant inhibition of edema swelling compared to free GE hydrogel and ketoprofen gel. The animals that were treated with ginger transethosome hydrogel showed a significant decrement in reactive oxygen species and prostaglandin E2 compared to untreated animals.Conclusion: Transethosomes might be a promising new vehicle for GE for effective skin permeation and anti-inflammation. To the best of our knowledge, this work is the first utilization of transethosomes laden into hydrogel as a novel transdermal delivery system of GE.Graphical Abstract: Keywords: nanovesicles, transethosomes, ginger, ex vivo permeation, transdermal delivery, inflammation

Methotrexate (MTX) is one of the most widely used cytotoxic chemotherapeutic agents, and it is used in the treatment of different autoimmune disorders. However, the clinical applications of MTX are limited by its hepatic toxicity. Hence, the present study was conducted to evaluate the efficacy of fasudil (Rho-Kinase inhibitor) in the amelioration of MTX hepatotoxicity and the possible underlying mechanisms. Experimentally, 32 male Sprague Dawley rats were used and divided into four groups: control, MTX (20 mg/kg, i.p., single dose), fasudil (10 mg/kg/day i.p.) for one week, and fasudil plus MTX. It was found that MTX significantly induced hepatitis and hepatocellular damage, as shown by abnormal histological findings and liver dysfunction (ALT and AST), with up-regulation of the inflammatory mediators NF-κB-p65 and IL-1β. Moreover, MTX remarkably disrupted oxidant/antioxidant status, as evidenced by malondialdehyde (MDA) up-regulation associated with the depletion of superoxide dismutase (SOD), catalase, and reduced glutathione (GSH) levels. Moreover, MTX reduced the hepatic expression of B-cell lymphoma 2 (Bcl-2). On the contrary, the i.p. administration of fasudil significantly ameliorated MTX hepatotoxicity by histopathological improvement, restoring oxidant/antioxidant balance, preventing hepatic inflammation, and improving the hepatic anti-apoptotic capability. Furthermore, fasudil hepatic concentration was determined for the first time using the validated RP-HPLC method. In conclusion, the present study revealed that fasudil has a reliable hepatoprotective effect against MTX hepatotoxicity with underlying antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. It also introduced a new method for the determination of fasudil hepatic tissue concentration using the RP-HPLC technique.

Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays pivotal role in tumour growth and angiogenesis. A novel series of naphtho[2',3':4,5]thiazolo[3,2-a]pyrimidine hybrids have been designed, synthesised and evaluated for their topo IIα/EGFR inhibitory and apoptotic inducer activities. Cytotoxicity of the synthesised hybrids was evaluated against MCF-7, A549 and HCT-116 cell lines. Of the synthesised hybrids, 6i, 6a and 6c experienced superior cytotoxic activity compared to doxorubicin and erlotinib against the tested cancer cells. The molecular mechanism of these hybrids revealed their ability to successfully inhibit topo IIα and EGFR activities in micromolar concentration and may serve as topo II catalytic inhibitor. Moreover, these hybrids significantly arrested cell cycle at G2/M phase together with increased p53, caspae-7, caspase-9 levels and Bax/Bcl-2 ratio. The synthesised hybrids showed efficient binding pattern in molecular docking study and have acceptable drug likeness characters. [ABSTRACT FROM AUTHOR]

Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays pivotal role in tumour growth and angiogenesis. A novel series of naphtho[2',3':4,5]thiazolo[3,2-a]pyrimidine hybrids have been designed, synthesised and evaluated for their topo IIα/EGFR inhibitory and apoptotic inducer activities. Cytotoxicity of the synthesised hybrids was evaluated against MCF-7, A549 and HCT-116 cell lines. Of the synthesised hybrids, 6i, 6a and 6c experienced superior cytotoxic activity compared to doxorubicin and erlotinib against the tested cancer cells. The molecular mechanism of these hybrids revealed their ability to successfully inhibit topo IIα and EGFR activities in micromolar concentration and may serve as topo II catalytic inhibitor. Moreover, these hybrids significantly arrested cell cycle at G2/M phase together with increased p53, caspae-7, caspase-9 levels and Bax/Bcl-2 ratio. The synthesised hybrids showed efficient binding pattern in molecular docking study and have acceptable drug likeness characters.

Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays pivotal role in tumour growth and angiogenesis. A novel series of naphtho[2',3':4,5]thiazolo[3,2- a ]pyrimidine hybrids have been designed, synthesised and evaluated for their topo IIα/EGFR inhibitory and apoptotic inducer activities. Cytotoxicity of the synthesised hybrids was evaluated against MCF-7, A549 and HCT-116 cell lines. Of the synthesised hybrids, 6i , 6a and 6c experienced superior cytotoxic activity compared to doxorubicin and erlotinib against the tested cancer cells. The molecular mechanism of these hybrids revealed their ability to successfully inhibit topo IIα and EGFR activities in micromolar concentration and may serve as topo II catalytic inhibitor. Moreover, these hybrids significantly arrested cell cycle at G2/M phase together with increased p53, caspae-7, caspase-9 levels and Bax/Bcl-2 ratio. The synthesised hybrids showed efficient binding pattern in molecular docking study and have acceptable drug likeness characters.