研究动态
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Trichostatin A对辐射引起的小鼠胃肠毒性和肠道微生物变化具有减轻和抗炎作用。

Mitigative and anti-inflammatory effects of Trichostatin A against radiation induced gastrointestinal toxicity and gut microbiota alteration in mice.

发表日期:2023 Aug 02
作者: Akshu Dahiya, Paban Kumar Agrawala, Ajaswrata Dutta
来源: Epigenetics & Chromatin

摘要:

放射線誘導的腸道損傷(RIGI)是腹部和盆腔放射治療的一個嚴重副作用,通常限制了對腸胃道和婦科癌症的治療。在意外的放射線或核災害情況下也會觀察到RIGI,迄今為止尚無批准的藥物可用於預防或緩解人體中的RIGI。曾在臨床試驗中用於癌症治療的上海衛星製藥服用的葉酸,被發現具有曲霉菌和抗真菌作用。本研究使用股體(腹部)照射小鼠模型,研究TSA對伽馬輻射引起的腸道毒性的緩解作用。檢查小鼠體重均值變化、腹瀉發生率、疾病活動指數和對輻射的存活情況。通過組織病理學和16S rRNA宏基因組定序分析糞便樣本來研究腸道結構異常和腸道菌群成分的變化。進行免疫印跡和生化分析來檢查蛋白質硝酸化、炎症介質表達、炎症細胞浸潤和促炎细胞因子的變化。將TSA用於C57Bl/6小鼠可改善輻射引起的體重損失,維持更好的健康狀態,降低疾病活動指數並促進存活。糞便DNA的16S rRNA定序表明TSA影響了糞便菌群動態,Firmicutes/Bacteriodetes比例出現了顯著變化。TSA有效緩解了腸道損傷,下調了輻射引起的腸道NF-κB、Cox-2、iNOS的表達,抑制了PGE2和蛋白質硝酸化水平。TSA還阻止了發炎腸道中NLRP3炎症體和炎性細胞的浸潤。隨後,腸道中的髓過氧化酶活性以及血清IL-18水平均顯著降低。這些發現證明了TSA抑制炎症介質,緩解腸道菌相失調,並促進輻射損傷腸道的結構修復。因此,TSA可被視為治療人類RIGI的潛在藥物。
Radiation-induced gastrointestinal injury (RIGI) is a serious side effect of abdominal and pelvic radiotherapy, which often limits the treatment of gastrointestinal and gynaecological cancers. RIGI is also observed during accidental radiological or nuclear scenarios with no approved agents available till date to prevent or mitigate RIGI in humans. Trichostatin A (TSA), an epigenetic modulator, has been currently in clinical trials for cancer treatment and is also well known for its antibiotic and antifungal properties.In this study, partial body (abdominal) irradiation mice model has been used to investigate the mitigative effect of TSA against gastrointestinal toxicity caused by gamma radiation. Mice were checked for alterations in mean body weight, diarrhea incidence, disease activity index and survival against radiation. Structural abnormalities in intestine and changes in microbiota composition were studied by histopathology and 16S rRNA sequencing of fecal samples respectively. Immunoblotting and biochemical assays were performed to check protein nitrosylation, expression of inflammatory mediators, infiltration of inflammatory cells and changes in pro-inflammatory cytokines.TSA administration to C57Bl/6 mice improved radiation induced mean body weight loss, maintained better health score, reduced disease activity index and promoted survival. The 16S rRNA sequencing of fecal DNA demonstrated that TSA influenced the fecal microbiota dynamics with significant alterations in the Firmicutes/Bacteriodetes ratio. TSA effectively mitigated intestinal injury, down-regulated NF-κB, Cox-2, iNOS, inhibited PGE2 and protein nitrosylation levels in irradiated intestine. The upregulation of NLRP3-inflammasome complex and infiltrations of inflammatory cells in the inflamed intestine were also prevented by TSA. Subsequently, the myeloperoxidase activity in intestine alongwith serum IL-18 levels was found reduced.These findings provide evidence that TSA inhibits inflammatory mediators, alleviates gut dysbiosis, and promotes structural restoration of the irradiated intestine. TSA, therefore, can be considered as a potential agent for mitigation of RIGI in humans.