RESUMO
Genetic susceptibility to two-stage skin carcinogenesis is known to vary significantly among different stocks and strains of mice. In an effort to identify specific protein changes or altered signaling pathways associated with skin tumor promotion susceptibility, a proteomic approach was used to examine and identify proteins that were differentially expressed in epidermis between promotion-sensitive DBA/2 and promotion-resistant C57BL/6 mice following treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). We identified 19 differentially expressed proteins of which 5 were the calcium-binding proteins annexin A1, parvalbumin α, S100A8, S100A9, and S100A11. Further analyses revealed that S100A8 and S100A9 protein levels were also similarly differentially upregulated in epidermis of DBA/2 versus C57BL/6 mice following topical treatment with two other skin tumor promoters, okadaic acid and chrysarobin. Pathway analysis of all 19 identified proteins from the present study suggested that these proteins were components of several networks that included inflammation-associated proteins known to be involved in skin tumor promotion (e.g. TNF-α, NFκB). Follow-up studies revealed that Tnf, Nfkb1, Il22, Il1b, Cxcl1, Cxcl2 and Cxcl5 mRNAs were highly expressed in epidermis of DBA/2 compared with C57BL/6 mice at 24h following treatment with TPA. Furthermore, NFκB (p65) was also highly activated at the same time point (as measured by phosphorylation at ser276) in epidermis of DBA/2 mice compared with C57BL/6 mice. Taken together, the present data suggest that differential expression of genes involved in inflammatory pathways in epidermis may play a key role in genetic differences in susceptibility to skin tumor promotion in DBA/2 and C57BL/6 mice.
Assuntos
Carcinógenos/toxicidade , Mediadores da Inflamação/metabolismo , Proteômica , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Animais , Western Blotting , Eletroforese em Gel Bidimensional , Feminino , Imunofluorescência , Predisposição Genética para Doença , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/patologia , Especificidade da Espécie , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
STUDY OBJECTIVES: To describe the crude prevalence of rapid eye movement (REM) sleep behavior disorder (RBD) following traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) in Veterans, given potential relationships between TBI, PTSD, RBD, and neurodegeneration. METHODS: Veterans (n = 394; 94% male; 54.4 ± 15.5 years of age) were prospectively/cross-sectionally recruited from the VA Portland Health Care System and completed in-lab video-polysomnography and questionnaires. TBI and PTSD were assessed via diagnostic screening and medical record review. Subjects were categorized into four groups after assessment of REM sleep without atonia (RSWA) and self-reported dream enactment: (1) "Normal," neither RSWA nor dream enactment, (2) "Other Parasomnia," dream enactment without RSWA, (3) "RSWA," isolated-RSWA without dream enactment, and (4) "RBD," RSWA with dream enactment. Crude prevalence, prevalence odds ratio, and prevalence rate for parasomnias across subjects with TBI and/or PTSD were assessed. RESULTS: Overall prevalence rates were 31%, 7%, and 9% for Other Parasomnia, RSWA, and RBD, respectively. The prevalence rate of RBD increased to 15% in PTSD subjects [age adjusted POR: 2.81 (1.17-4.66)] and to 21% in TBI + PTSD subjects [age adjusted POR: 3.43 (1.20-9.35)]. No subjects met all diagnostic criteria for trauma-associated sleep disorder (TASD), and no overt dream enactment was captured on video. CONCLUSIONS: The prevalence of RBD and related parasomnias is significantly higher in Veterans compared with the general population and is associated with PTSD and TBI + PTSD. Considering the association between idiopathic-RBD and synucleinopathy, it remains unclear whether RBD (and potentially TASD) associated with PTSD or TBI + PTSD similarly increases risk for long-term neurologic sequelae.