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吉瑪慢病毒再次助力我國優秀科學家登頂國際頂級期刊《CELL》

2020年9月14日,中山大學孫逸仙紀念醫院 蘇士成博士、許小丁博士及中山大學附屬第三醫院 高志良教授作為共同通訊作者,在國際頂尖學術期刊? Cell 在線發表題為:Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output 的研究論文。該研究確定了一種 線粒體特異性circRNA——SCAR,在 非酒精性脂肪性肝炎(NASH)中表達下調,向線粒體特異性遞送SCAR,可降低線粒體活性氧 (mROS)輸出,減輕炎癥,可作為NASH的治療靶標。

非酒精性脂肪性肝炎(NASH)是 非酒精性脂肪性肝?。∟AFLD)的炎癥亞型,伴有肝脂肪變性以及肝細胞損傷和炎癥的證據,伴或不伴肝纖維化。隨著時間的推移, NASH可能進展為肝硬化、終末期肝病或需要肝移植。非酒精性脂肪性肝炎患者的肝病致殘率和病死率顯著高于單純性脂肪肝。

線粒體(mitochondrion),是細胞的“ 能量工廠”,線粒體發揮重要的細胞功能,通過氧化磷酸化 (OXPHOS)調節能量供應,執行細胞死亡以及Ca離子和活性氧(ROS)的細胞內信號轉導,線粒體 在免疫代謝疾病中也起到了關鍵作用。

研究團隊通過對非酒精性脂肪性肝炎(NASH)患者肝成纖維細胞的circRNA表達譜分析,發現線粒體circRNA占NASH成纖維細胞下調circRNA的相當一部分。觀察到位于線粒體中的 circRNA——SCAR,抑制線粒體活性氧 (mROS)輸出和成纖維細胞活化。由PGC-1α介導的circRNA SCAR與ATP5B結合,并通過構建慢病毒shRNA干擾阻斷CypD-mPTP相互作用而關閉 線粒體通透轉運孔道(mPTP)。脂質超載通過內質網應激誘導的 C/EBP-同源蛋白(CHOP)抑制PGC-1α。動物體內實驗也表明,靶向circRNA SCAR可減輕高脂飲食引起的肝硬化和胰島素抵抗。而在臨床上,circRNA SCAR與脂肪變性到NASH的進展有關。

通過該研究,我國科學家又進步確定了一種線粒體中的新型circRNA——SCAR,可作為非酒精性脂肪性肝炎(NASH)的治療靶標,為我們今后攻克該疾病提供了新的研究方向。

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Figure 5. circRNA SCAR Shuts Down mPTP by Preventing CypD-mPTP Interaction

(A) Normal fibroblasts were treated with palmitate in the presence of mito-NP containing empty vectors (Vector), wild-type (SCAR), or mutated (SCAR-mut) circRNA SCAR overexpression vectors. Their mPTP opening was measured by calcein loading/CoCl2 quenching (n = 4 patients).

(B) In vitro RNA/protein interaction assay between recombinant ATP5B and indicated biotin-labeled circRNAs (n = 3).

(C) Normal fibroblasts were treated with palmitate in the presence of mito-NP containing wild-type or mutated circRNA SCAR overexpression vectors. Representative western blots of CypD and ATP5B (subunit of ATP synthase) in the ATP synthase-immunoprecipitated lysates are shown (n = 3 patients).

(D–G) Normal fibroblasts were treated with palmitate in the presence of mito-NP containing wild-type or mutated circRNA SCAR overexpression vectors. In some experiments, fibroblasts were pre-transduced with CypD-shRNAs.

(D) mPTP opening (upper) and ΔΨm (lower) were measured by calcein loading/CoCl2 quenching and JC-1 staining, respectively (n = 3 patients).

(E) Cytosolic ROS levels were detected by cytoORP via confocal microscopy. The 405/488 nm excitation ratio was quantitated (n = 5 patients).

(F) Fibroblast contractility in collagen matrices (n = 3 patients).

(G) Indicated cytokines were examined by ELISA (n = 4 patients).

注:材料方法中shRNA and siRNA Mediated Silencing

For shRNA transduction, a lentiviral vector plasmid pLKO.1-puro (GenePharma Inc, Shanghai, China) was used to construct the stable clones.?

吉瑪基因病毒產品近幾年已經連續多次助力我國科學家在頂級期刊CNS上發表重要科學論文(參見相關鏈接https://mp.weixin.qq.com/s/PdkI8YelrpYLRupy-lFz9Q)。近期我們又推出了新的產品方案和促銷方案,歡迎大家積極關注索取相關產品和服務信息。吉瑪基因是您攀登科學高峰的永久忠實伙伴。




參考文獻

1. Zhao et al., Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output, Cell (2020), https://doi.org/10.1016/j.cell.2020.08.009
2. C.Y. Yu et al.,The circular RNA circBIRC6 participates in the molecular circuitry controlling human pluripotency. Nat. Commun., 8 (2017), p. 1149


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