RESUMEN
The ciliary muscle constitutes a crucial element in refractive regulation. Investigating the pathophysiological mechanisms within the ciliary muscle during excessive contraction holds significance in treating ciliary muscle dysfunction. A guinea pig model of excessive contraction of the ciliary muscle induced by drops pilocarpine was employed, alongside the primary ciliary muscle cells was employed in in vitro experiments. The results of the ophthalmic examination showed that pilocarpine did not significantly change refraction and axial length during the experiment, but had adverse effects on the regulatory power of the ciliary muscle. The current data reveal notable alterations in the expression profiles of hypoxia inducible factor 1 (HIF-1α), ATP2A2, P53, α-SMA, Caspase-3, and BAX within the ciliary muscle of animals subjected to pilocarpine exposure, alongside corresponding changes observed in cultured cells treated with pilocarpine. Augmented levels of ROS were detected in both tissue specimens and cells, culminating in a significant increase in cell apoptosis in in vivo and in vitro experiments. Further examination revealed that pilocarpine induced an increase in intracellular Ca2+ levels and disrupted MMP, as evidenced by mitochondrial swelling and diminished cristae density compared to control conditions, concomitant with a noteworthy decline in antioxidant enzyme activity. However, subsequent blockade of Ca2+ channels in cells resulted in downregulation of HIF-1α, ATP2A2, P53, α-SMA, Caspase-3, and BAX expression, alongside ameliorated mitochondrial function and morphology. The inhibition of Ca2+ channels presents a viable approach to mitigate ciliary cells damage and sustain proper ciliary muscle function by curtailing the mitochondrial damage induced by excessive contractions.
Asunto(s)
Apoptosis , Calcio , Senescencia Celular , Pilocarpina , Animales , Pilocarpina/farmacología , Cobayas , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Senescencia Celular/efectos de los fármacos , Cuerpo Ciliar/metabolismo , Masculino , Células Cultivadas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Dexamethasone (DEX) has been demonstrated to inhibit the inflammatory corneal neovascularization (CNV). However, the therapeutic efficacy of DEX is limited by the poor bioavailability of conventional eye drops and the increased risk of hormonal glaucoma and cataract associated with prolonged and frequent usage. To address these limitations, we have developed a novel DEX-loaded, reactive oxygen species (ROS)-responsive, controlled-release nanogel, termed DEX@INHANGs. This advanced nanogel system is constructed by the formation of supramolecular host-guest complexes by cyclodextrin (CD) and adamantane (ADA) as a cross-linking force. The introduction of the ROS-responsive material, thioketal (TK), ensures the controlled release of DEX in response to oxidative stress, a characteristic of CNV. Furthermore, the nanogel's prolonged retention on the corneal surface for over 8 h is achieved through covalent binding of the integrin ß1 fusion protein, which enhances its bioavailability. Cytotoxicity assays demonstrated that DEX@INHANGs was not notably toxic to human corneal epithelial cells (HCECs). Furthermore, DEX@INHANGs has been demonstrated to effectively inhibit angiogenesis in vitro. In a rabbit model with chemically burned eyes, the once-daily topical application of DEX@INHANGs was observed to effectively suppress CNV. These results collectively indicate that the nanomedicine formulation of DEX@INHANGs may offer a promising treatment option for CNV, offering significant advantages such as reduced dosing frequency and enhanced patient compliance.
Asunto(s)
Neovascularización de la Córnea , Dexametasona , Especies Reactivas de Oxígeno , Animales , Conejos , Neovascularización de la Córnea/tratamiento farmacológico , Dexametasona/administración & dosificación , Dexametasona/farmacocinética , Humanos , Especies Reactivas de Oxígeno/metabolismo , Nanogeles/química , Preparaciones de Acción Retardada , Córnea/metabolismo , Córnea/efectos de los fármacos , Masculino , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/química , Línea Celular , Polietilenglicoles/química , Polietilenglicoles/administración & dosificación , Administración Oftálmica , Adamantano/administración & dosificación , Adamantano/análogos & derivados , Ciclodextrinas/química , Antiinflamatorios/administración & dosificación , Polietileneimina/química , Polietileneimina/administración & dosificación , Liberación de FármacosRESUMEN
Natural polysaccharides extracted from plants have received increasing attention due to their rich bioactivity. In our study, peach gum polysaccharides (PGPs) were extracted by water extraction-alcohol precipitation method. PGPs are typical pyranose polysaccharides with a mean molecular weight of 3.68 × 106 g/mol. The antioxidant activity and hepatoprotective capacity of PGPs were studied. In vitro, assays showed that PGPs scavenged DPPH, OH, and O2- in a dose-dependent manner. PGPs exhibited antioxidative properties against alcohol-induced HL7702 cells, as evidenced by the normalization of MDA, SOD, ROS, and GSH levels. To further elucidate the hepatoprotective mechanism of PGPs, we carried out in vivo experiments in male mice. PGPs exerted hepatoprotective effects in alcohol liver disease (ALD) mice by exerting antioxidant effects, decreasing the inflammatory response and modulating lipid metabolism. In addition, metabolomic analysis indicated that PGPs mainly regulate D-glutamine and D-glutamate metabolism, alanine, aspartate and glutamate metabolism, and arginine biosynthesis to promote hepatic metabolism and maintain body functions. Overall, this study revealed that the hepatoprotective mechanism of PGPs against ALD might be associated with the regulation of oxidative stress and lipid metabolism.
RESUMEN
Here, Ru clusters supported on nitrogen-doped hollow carbon spheres show a remarkable activity and durability toward the hydrogen oxidation reaction (HOR) and H2-O2 fuel cell performance in alkaline media. Theoretical simulations indicate that Ru clusters endow a thermodynamically favourable HOR kinetics and an optimal hydrogen adsorption affinity.