The role of Hrd1 in ultraviolet (UV) radiation induced photoaging.

The purpose of the present study was to evaluate the role of Hrd1 in the ultraviolet (UV) radiation induced photoaging and explore its potential mechanism. The nude mice were exposed to the UVA/UVB irradiation for 10 weeks. The animals were subcutaneously injected with AAV5-NC, Hrd1-shRNA-AAV5, or Hrd1-overexpression-AAV5. The HSF cells were also transfected with Ad-NC, Ad-shRNA-Hrd1, or Ad-Hrd1, and irradiated by UVA/UVB stimulation. The clinical skin samples were harvested for detecting Hrd1 and IGF-1R expressions. As a result, the knockdown of Hrd1 attenuated the histopathological alteration and collagen degradation in UV-induced nude mice. The inhibition of Hrd1 by Hrd1-shRNA-AAV5 and Ad-shRNA-Hrd1 inhibited the Hrd1 expression and promoted IGF-1R, Type I collagen and type III collagen in mice and HSF cells. The overexpression of Hrd1 exerted the reverse effect. The Co-IP assay also indicated the interaction between Hrd1 and IGF-1R. Hrd1-mediated IGF-1R downregulation and collagen degradation were also observed in clinical skin samples. In conclusion, the present results demonstrated that Hrd1 degraded IGF-1R and collagen formation in UV-induced photoaging.

ATRA protects skin fibroblasts against UV­induced oxidative damage through inhibition of E3 ligase Hrd1.

All­trans retinoic acid (ATRA) can protect fibroblasts against ultraviolet (UV)­induced oxidative damage, however, its underlying molecular mechanism is still unclear. The present study aimed to investigate the role of 3­hydroxy­3­methylglutaryl reductase degradation (Hrd1) in the protective effect of ATRA on human skin fibroblasts exposed to UV. The expression of Hrd1 in human or mice skin was assessed by immunohistochemistry (IHC) staining and western blot analysis. Hrd1 siRNA (si­Hrd1) and Hrd1 recombinant adenoviruses (Ad­Hrd1) were used to downregulate and upregulate Hrd1 expression in fibroblasts, respectively. The interaction between Hrd1 and NF­E2­related factor 2 (Nrf2) was assessed by co­immunoprecipitation (co­IP) and immunofluorescence analysis. The results revealed that Hrd1 expression was increased but Nrf2 expression was decreased in UV­exposed human skin fibroblasts. In addition, ATRA could reverse the increase of Hrd1 expression induced by UV radiation in vivo and in vitro. ATRA or knockdown of Hrd1 could increase Nrf2 expression in fibroblasts exposed to UV radiation, and Hrd1 could directly interact with Nrf2 in skin fibroblasts. Notably, overexpression of Hrd1 abolished the protective effect of ATRA on the UV­induced decrease of Nrf2 expression, the production of reactive oxygen species (ROS) and the decrease of cell viability. In conclusion, the present data demonstrated that ATRA protected skin fibroblasts against UV­induced oxidative damage through inhibition of E3 ligase Hrd1.

A case report of toxic epidermal necrolysis associated with AZD-9291.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a strain of small molecule inhibitors mainly used to treat the metastatic non-small cell lung cancer. Their predominant adverse effect is skin toxicity, usually manifested as acneiform rash, skin fissure, xerosis, and paronychia. Severe epidermal necrosis and exfoliation rarely occur. As one of the new generation of epidermal growth factor receptor-tyrosine kinase inhibitors, AZD-9291 is claimed to have better efficacy and fewer side effects, particularly appropriate for patients with EGFR T790M mutation. Herein we report a 51-year-old man who developed a large area of skin necrosis and was diagnosed with toxic epidermal necrolysis after AZD-9291 ingestion.