RESUMEN
A negative impact of finasteride on fertility has been reported, in which over production of reactive oxygen species and apoptosis were implicated. Hesperidin, a plant-derived bioflavonoid with antioxidant and anti-apoptotic effects, may mitigate these adverse effects. In order to investigate the possible protective role of hesperidin against finasteride-induced seminiferous tubules toxicity in adult male Wistar rats, 60 rats were randomized into five groups (I-V) receiving distilled water, 0.5% sodium carboxymethylcellulose solution, hesperidin, finasteride, and combined hesperidin and finasteride respectively. Testicular weight, sperm count and motility were determined. Testicular tissue homogenates were prepared to measure the level of malondialdehyde (MDA), total antioxidant capacity (TAC), reduced glutathione (GSH) and the gene expression of caspase-3 and B-cell lymphoma 2 (Bcl2). Testes were processed for light and electron microscopic evaluation. Johnsen score was calculated. Administration of finasteride resulted in significantly decreased testicular weights, sperm count and motility, Johnsen score, tissue levels of TAC and GSH together with significant increase in tissue MDA. Gene expression revealed significantly increased caspase-3 and decreased Bcl2. Furthermore, finasteride disrupted the seminiferous tubules, causing degenerative changes affecting Sertoli cells and spermatogenic cells. Co-administration of hesperidin with finasteride resulted in improvement in testicular weights, TAC, GSH, Bcl2, Johnsen score, sperm count and motility as well as preservation of the structure of the seminiferous tubules. To conclude, hesperidin was found to have a protective potential on finasteride-induced oxidative stress, apoptosis and testicular structural damage.
Asunto(s)
Hesperidina , Testículo , Masculino , Ratas , Animales , Ratas Wistar , Hesperidina/metabolismo , Hesperidina/farmacología , Antioxidantes/farmacología , Antioxidantes/metabolismo , Finasterida/toxicidad , Finasterida/metabolismo , Caspasa 3/genética , Caspasa 3/metabolismo , Semen/metabolismo , Túbulos Seminíferos , Espermatozoides , Estrés Oxidativo , Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
Cartilage deterioration is the hallmark of osteoarthritis (OA). Rapid clearance of intra-articularly injected drugs and inherent cartilage barrier properties represent enormous challenges facing the effective local OA therapy. Rhein (RH), a dihydroxy-anthraquinone acid molecule, possess a potential chondroprotective effect. However, RH suffers from poor oral bioavailability besides its gastrointestinal side effects. Herein, for the first time, we exploited cationic carriers to target anionic cartilage matrix to create a RH-reservoir within the cartilage matrix, improving RH therapeutic efficacy with reduced side effects. Firstly, we improved RH lipophilic characteristics employing hydrophobic ion pairing (HIP) to be efficiently loaded within lipid nanoparticles with slow-release properties. RH-HIP integrated solid lipid nanoparticles (RH-SLNs) rapidly penetrated through cartilage tissue and lasted for 3 weeks into healthy and arthritic rat joints. Furthermore, RH-SLNs significantly inhibited inflammatory response, oxidative stress and cartilage deterioration in MIA-arthritic rats. In conclusion, intra-articular cationic RH-SLNs represented a meaningful step towards OA therapy.
Asunto(s)
Cartílago Articular , Osteoartritis , Animales , Antraquinonas , Liposomas , Nanopartículas , Osteoartritis/tratamiento farmacológico , RatasRESUMEN
Rhein (RH), a natural chondroprotective agent, suffers from poor systemic availability (20-25%) after oral administration concomitant to side effects on the gastrointestinal tract and liver. We present a new approach for non-invasive local targeted delivery of rhein to ameliorate cartilage deterioration employing cartilage-homing phospholipids nanocarriers. This is the first work to elaborate RH loaded transphytosome (RH-T-PHY) as novel nanovesicular systems for transdermal drug delivery based on an advantageous hybrid between phytosomes and transfersomes or bilosomes. Here, we developed transphytosomes through incorporating various edge activators (EAs) such as Tween 80, Span 80 and sodium deoxycholate into the lipid bilayer of RH phytosomes to affix the flexibility. RH-T-PHY with high flexibility and entrapment efficacy showed the highest significant skin permeation compared to conventional phytosomes. Additionally, RH-T-PHY have a magnificent potential in maintaining high chondroprotective activity as demonstrated by enhanced repair, regeneration of chondrocytes and GAG formation in MIA-induced osteoarthritis (OA) rat model. Besides, histological examination of vital organs revealed the formulation safety. Confocal laser microscopy images revealed the highest drug availability in the articular cartilage of RH-T-PHY treated group. Conclusively, novel RH-T-PHY can serve as a promising alternative means for delivery of chondroprotective drugs for effective non-invasive local therapy of OA.