RESUMEN
BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) is implicated in cancer progression, but its role and associated molecular mechanism in the sorafenib sensitivity of hepatocellular carcinoma cells (HCC) remains elusive. METHODS: Human HCC cell lines Hep3B and HepG2 were treated with sorafenib alone or combined with activator or inhibitor of ferroptosis. Cell viability assay, reactive oxygen species (ROS) assay, lactate dehydrogenase (LDH) assay and western blot were used to study the regulatory mechanism of SPARC on HCC cells. RESULTS: Overexpression of SPARC enhanced the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Depletion of SPARC decreased the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Moreover, overexpression of SPARC significantly induced LDH release, whereas depletion of SPARC suppressed the release of LDH in Hep3B and HepG2 cells. Inhibition of ferroptosis exerted a clear inhibitory role against LDH release, whereas activation of ferroptosis promoted the release of LDH in HCC cells, as accompanied with deregulated expression of ferroptosis-related proteins. Furthermore, overexpression of SPARC induced oxidative stress, whereas depletion of SPARC suppressed the production of ROS. Deferoxamine (DFX)-induced inhibition of ferroptosis suppressed the production of ROS, while activation of ferroptosis promoted the contents of ROS in HCC cells exposed to sorafenib. CONCLUSION: Our findings give a better understanding of ferroptosis and its molecular mechanism in HCC cells that is regulated by SPARC in response to sorafenib.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Ferroptosis/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Osteonectina/metabolismo , Sorafenib/farmacología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: The sensitization and elicitation phases are involved in the immunopathogenesis of contact hypersensitivity (CHS). Langerhans cells (LCs) are believed to play pivotal roles in the sensitization stage of CHS. Local hyperthermia on skin induces the migration as well as maturation of epidermal LCs. Although fever-range whole body hyperthermia and local hyperthermia at 43°C prior to sensitization were reported to suppress CHS, the effects of different temperatures and the timing sequence of local hyperthermia on CHS have not been tackled. METHODS: Local hyperthermia was applied to murine dorsal skin 3 days prior to, concurrent with, or 2 days post sensitization with fluorescein isothiocyanate (FITC) in BALB/c mice. Local hyperthermia temperatures at 37°C, 39°C, 41°C and 43°C were applied to mouse dorsal skin and the severity of CHS was calculated by measuring the swelling response of the challenged ears. RESULTS: Local hyperthermia at 39°C, 41°C and 43°C prior to sensitization reduced the severity of CHS, as compared with that at 37°C. The suppression of CHS was temperature dependent in that higher temperature had a stronger effect. On the contrary, the hyperthermia treatments, either concurrent with or post-sensitization, resulted in an enhanced temperature-dependent ear swelling response. CONCLUSIONS: The severity of murine CHS could be influenced by local hyperthermia at the sensitization stage in a temperature dependent manner. The temporal effect of local hyperthermia suggested a novel factor in interpreting the severity of allergic contact dermatitis.
Asunto(s)
Dermatitis por Contacto/terapia , Hipertermia Inducida , Animales , Femenino , Células de Langerhans/fisiología , Ratones , Ratones Endogámicos BALB CRESUMEN
A study was conducted to determine the number and distribution of interstitial cells lining the epidermis of normal human skin from various anatomical locations. Five to seven normal human skin specimens per each anatomical site were collected from surgical specimens, mostly with pigmented nevi. Ten anatomical locations were classified; and a total of 65 normal human skin samples were evaluated. The number of interstitial cells lining the epidermis was quantified under light microscopy using a computer-assisted image analyzer. Two types of interstitial cells were recognized beneath the dermo-epidermal junction of normal human skin: cells containing oval nuclei and spindle-shaped cells containing elongated nuclei. As for the number of oval cells, no significant difference was found among the anatomical locations. In contrast, significantly greater numbers of spindle-shaped cells were found in the palm (4.11 + 1.24; p < 0.01), sole (3.52 + 0.83; p < 0.001) and buttock (2.52 + 0.49; p < 0.01), compared with those in the anterior trunk (0.60 + 0.22). In normal skin of the palm and sole, the number of spindle-shaped cells located beneath the apices of rete ridges (7.35 + 1.56) was significantly greater than along the dermal papillae (1.39 + 0.39, p < 0.01). However, cells containing oval nuclei also predominated beneath the apices of rete ridges, but the difference was not significant. In summary, the present study demonstrated that the number of spindle-shaped cells, quantified by H & E staining, was significantly greater beneath the apices of rete ridges than in dermal papillae. The number was greater in palm and sole skin compared with other samples of normal human skin. This data may relate to the glabrous nature of palm and sole skin.