Combination of ERK and autophagyinhibition as a treatment approach for pancreatic cancer.

ARS-1620 purchased from MCE.

胰腺導(dǎo)管腺癌(PDAC)的特征是 KRAS 和自噬依賴的致瘤生長，但 KRAS 在自噬中的作用尚未確定。令人驚訝的是，研究人員發(fā)現(xiàn) KRAS 的抑制增加了自噬通量，其效應(yīng)物 ERK MAPK 的藥理抑制也增加了自噬通量。此外，研究人員還證明 KRAS 抑制或 ERK 抑制都會降低糖酵解和線粒體功能。因此推測， ERK 抑制可能因此增強PDAC 對自噬的依賴，部分破壞其他 KRAS 或 ERK 驅(qū)動的代謝過程。研究人員發(fā)現(xiàn)自噬抑制劑氯喹與特異性自噬調(diào)節(jié)因子的遺傳或藥理抑制協(xié)同增強了 ERK 抑制劑介導(dǎo) kras 驅(qū)動的 PDAC 抗腫瘤活性的能力。進而得出結(jié)論，同時阻斷 ERK MAPK 和自噬過程的藥物抑制劑組合可能是治療 PDAC 的有效方法。

Researchers show that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. Therefore,researchers speculated that ERK inhibition might enhance PDAC dependence onautophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specificautophagy regulators synergistically enhanced the ability of ERK inhibitors tomediate antitumor activity in KRAS-driven PDAC. Accordingly, combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition maybe effective treatments for PDAC.

Cryo-EM Structure and Assembly of anExtracellular Contractile Injection System.

Protease Inhibitor Cocktail purchased from MCE.

細(xì)胞質(zhì)中出現(xiàn) DNA，通常是微生物感染的一種跡象，可通過循環(huán) GMP-AMP 合成酶(cGAS)快速檢測到，從而引發(fā)抗感染免疫反應(yīng)。然而，自我 DNA 對 cGAS 的慢性激活會導(dǎo)致嚴(yán)重的自身免疫性疾病，目前尚無有效的治療方法。重要的是，證明阿司匹林可以直接乙酰化 cGAS，并有效抑制 cGAS 介導(dǎo)的免疫反應(yīng)。最后，研究人員證明阿司匹林可以有效抑制 aicardii - goutieres 綜合征(AGS)患者細(xì)胞和 AGS 小鼠模型中自我 DNA 誘導(dǎo)的自身免疫。因此，研究表明乙酰化有助于 cGAS 的活性調(diào)節(jié)，并為治療 DNA 介導(dǎo)的自身免疫性疾病提供了一種潛在的治療方法。

Researchers report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. cGAS isdeacetylated in response to DNA challenges. Importantly, we show that aspirincan directly acetylate cGAS and efficiently inhibit cGAS-mediated immune responses. Finally, researchers demonstrate that aspirin can effectivelysuppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome (AGS) patient cells and in an AGS mouse model. Consequently, the study reveals that acetylation contributes to cGAS activity regulation and provides a potentialtherapy for treating DNA-mediated autoimmune diseases.