RESUMO
Histone post-translational modifications (PTMs) have been shown to be highly associated with inflammation response, suggesting a therapeutic significance of pharmacologically editing histone PTMs. Currently reported anti-inflammation small-molecules mainly target histone PTMs writers or erasers for methylation, phosphorylation, and acetylation. Although histone chaperones also appear to be involved in inflammation signaling cascades, whether small-molecules could target histone chaperones to show anti-inflammation effects has still been rarely discovered. In this study, natural product artone was found to show obvious inhibitory effects on microglia-mediated neuroinflammation by directly targeting ASF1a, which is a histone-remodeling chaperone. Mechanism study revealed that artone modulated histone H3 PTMs profile by down-regulating acetylation and trimethylation modification levels at sites K4, K9, K18 and K27. Artone-dependent regulations on PTMs further caused an effective inhibition on transcription factor NF-κB assembling to promoters of pro-inflammatory cytokine genes including Tnf-α, Il-6 and Rgs3, indicating a distinctive anti-neuroinflammation mechanism. Collectively, we reported artone as the first small-molecule targeting histone-remodeling chaperone ASF1a for anti-neuroinflammation. Moreover, these findings broaden our knowledge of histone chaperone as a druggable target protein for neuroinflammation inhibition, and open a new avenue to novel therapy strategy for inflammation-associated neurological disorders.
Assuntos
Artemisia/química , Proteínas de Ciclo Celular/metabolismo , Chaperonas de Histonas/metabolismo , Histonas/metabolismo , Lipopolissacarídeos/farmacologia , Microglia/citologia , Microglia/efeitos dos fármacos , Chaperonas Moleculares/metabolismo , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Acetilação/efeitos dos fármacos , Animais , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inflamação/metabolismo , Metilação/efeitos dos fármacos , Camundongos , Microglia/metabolismo , Chaperonas Moleculares/antagonistas & inibidores , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: This meta-analysis was performed to assess the efficacy of cryotherapy and nail solution (NS) use in preventing nail toxicity (NT) induced by taxane-based chemotherapy. METHODS: PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov registry databases were searched for relevant studies published up to December 2018. The primary outcome was taxane-induced NT. Secondary outcomes were skin toxicity (ST), time to toxicity and patient comfort. RESULTS: We reviewed three randomised control trials and six prospective studies with 708 patients. For meta-analysis, taxane-induced NT grading was compared. NT and ST were significantly lower in the cryotherapy patients than in the controls (grade 1 NT: risk ratio [RR] = 0.51, 95% confidence interval [CI] = 0.30-0.89; grade 2-3 NT: RR = 0.36, 95% CI = 0.11-1.12; total NT: RR = 0.49; 95% CI = 0.30-0.79; ST: RR = 0.46, 95% CI = 0.33-0.64). The NS-treated patients exhibited significantly lower NT than the controls. CONCLUSIONS: Nail solution-treated or cryotherapy patients exhibited lower NT incidence and severity associated with taxane-based chemotherapy than the controls. For patients who can afford and comply with NS use or cryotherapy, these measures represent effective prophylactic management for taxane-induced NT and improve their quality of life and functional statuses. Further studies are needed to establish the routine usage protocols, long-term efficacy and safety for these interventions.