RESUMEN
Blood transfusion-requiring diseases such as sickle cell anemia and thalassemia are characterized by an imbalance between iron intake and excretion, resulting in an iron overload (IOL) disorder. Hepatotoxicity is prevalent under the IOL disorder because of the associated hepatocellular redox and inflammatory perturbation. The current work was devoted to investigate the potential protection against the IOL-associated hepatotoxicity using chrysin, a naturally-occurring flavone. IOL model was created in male Wistar rats by intraperitoneal injection of 100â¯mg/kg elemental iron subdivided on five equal injections; one injection was applied every other day over ten days. Chrysin was administered in a daily dose of 50â¯mg/kg over the ten-day iron treatment period. On day eleven, blood and liver samples were collected and subjected to histopathological, biochemical, and molecular investigations. Chrysin suppressed the IOL-induced hepatocellular damage as revealed by decreased serum activity of the intracellular liver enzymes and improved liver histological picture. Oxidative damage biomarkers, and pro-inflammatory cytokines were significantly suppressed. Mechanistically, the levels of the redox and inflammation-controlling proteins SIRT1 and PPARγ were efficiently up-regulated. The liver iron load, NLRP3 inflammasome activation, and NF-κB acetylation and nuclear shift were significantly suppressed in the iron-intoxicated rats. Equally important, the level of the antioxidant protein Nrf2 and its target HO-1 were up-regulated. In addition, chrysin significantly ameliorated the IOL-induced apoptosis as indicated by reduction in caspase-3 activity and modulation of BAX and Bcl2 protein abundance. Together, these findings highlight the alleviating activity of chrysin against the IOL-associated hepatotoxicity and shed light on the role of SIRT1, NLRP3 inflammasome, and Nrf2 signaling as potential contributing molecular mechanisms.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Flavonoides , Inflamasomas , Factor 2 Relacionado con NF-E2 , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas Wistar , Transducción de Señal , Sirtuina 1 , Animales , Sirtuina 1/metabolismo , Masculino , Flavonoides/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Transducción de Señal/efectos de los fármacos , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Ratas , Hierro/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Estrés Oxidativo/efectos de los fármacos , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/complicacionesRESUMEN
With recent progress in the manufacture and applications of nickel oxide nanoparticles (NiO NPs), concerns about their adverse effects are increasing. Hesperidin (HSP) is a citrus flavonoid that has a potent anti-inflammatory, antioxidant and free radical scavenging activities. This study aims to investigate the protective effect of HSP against testicular and spermatological damages induced by NiO NPs in male rats. Forty rats were randomly and equally divided into four groups: control, NiO NPs, HSP and NiO NPs + HSP. NiO NPs (100 mg/kg) and/or HSP (100 mg/kg) were given daily by gavage for 60 days. Exposure to NiO NPs induced marked reproductive toxicity in male rats that was manifested by increased sperm abnormalities and deterioration of sperm motility, count and viability. NiO NPs also increased lipid peroxidation and negatively affected the cellular antioxidant defense system in the testis of rats. The level of serum testosterone hormone was increased in NiO NPs-exposed rats. qPCR showed a marked downregulation in expression of steroidogenesis-related genes (CYP11A1, HSD3B and STAR) and a significant upregulation in expression of apoptosis-related gene (caspase-9) in testicular tissue of rats. Various pathological lesions and an increase in the number of PCNA-positive immune-reactive cells were also noticed in the testis of NiO NPs-exposed rats. Co-administration of HSP significantly ameliorated most of the NiO NPs-induced testicular damages and improved male fertility in rats.