ABSTRACT
Three prime repair exonuclease 1 (TREX1), also known as DNase IE, is a major 3'-5' restriction exonuclease in most of tissues and cell types of the mammals. The exonuclease activity of TREX1 plays an essential role in maintaining the immune tolerance of the innate immune system, which avoids the excessive activation of the innate immune system and massive production of auto-antibodies induced by the abnormal accumulation of cytosolic DNA. cGAS-STING signaling was identified as an important innate immune response to pathogens and maintained cellular environmental homeostasis. TREX1 prevents occasional leakage of nuclear DNA into the cytosol, which activates cGAS and triggers the downstream type I interferons cascade. Mutations of human TREX1 cause a series of autoimmune diseases, such as Aicardi-Goutieres syndrome (AGS), Familial chilblain lupus (FCL), Systemic lupus erythematosus (SLE) and Leukodystrophy-related retinopathy (RVCL). Besides, TREX1 inhibits the innate immune response to human immunodeficiency virus type 1 (HIV-1) and plays an important role in mediating the viral immune evasion. Moreover, TREX1 acts as an upstream regulator of the DNA sensing pathway, which maintains tumor immune tolerance and prevents cell senescence. Here, we focus on the immune regulation of TREX1 and demonstrate the role of TREX1 in autoimmune diseases, HIV-1 infection, cancer and cell senescence to provide the basic theoretical guidance for human disease therapy.
ABSTRACT
Safranal, a main component of Crocus sativus, is suggested to have neuroprotective effects. The aim of this study was to investigate the effect of safranal and nanostructured lipid vehicle (NLV) carried safranal in acute and chronic experimental mice models of epilepsy. In PILO acute seizure model, safranal dose-dependently extended latency to generalized seizure, decreased the highest seizure stages and the number of generalized seizures. Moreover, NLV carried safranal further enhanced the anti-seizure effect, which is comparable to the action of sodium valproate. Meanwhile, NLV carried safranal reduced and delayed the electroencephalogram spectra power after pilocarpine injection. In histological aspect, safranal dose-dependently reduced the loss of neurons induced by seizure and NLV system further improved this protection at the same dose. In MES acute model, safranal markedly increased the electroconvulsive threshold, where NLV further improved its effect. In PTZ chronic seizure model, NLV carried safranal significantly delayed the kindling rate of progress and the time it took to reach generalized seizures as compared to NLV control group. In conclusion, this study indicates that safranal inhibits generalized seizure in acute and chronic epilepsy models in mice and NLV can enhance this effect. So, NLV carried safranal may have potential value in treatment of generalized epilepsy.
