Hydrogen sulphide exacerbates acute pancreatitis by over-activating autophagy via AMPK/mTOR pathway.
Hydrogen sulphide exacerbates acute pancreatitis by over-activating autophagy via AMPK/mTOR pathway.
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DOI：
10.1111/jcmm.12928
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发表时间：
2016-12
影响因子：
5.3
通讯作者：
Sun B
中科院分区：
文献类型：
--
作者：
Ji L;Li L;Qu F;Zhang G;Wang Y;Bai X;Pan S;Xue D;Wang G;Sun B
先前，我们已经证明，在急性胰腺炎（AP）期间，硫化氢（H2S）可能通过抑制细胞凋亡并随后促进坏死优于细胞凋亡而具有促炎作用。在这项研究中，我们试图研究H2S在AP过程中的有害影响，特别是它对受损自噬的调节。在AP诱导后，通过氢硫化钠（NaHS）或DL -丙基甘氨酸（PAG）人为干预H2S的培养水平。自噬空泡的积累和腺泡内胰蛋白酶原的提前激活表明AP过程中自噬的损害，NaHS均加重了自噬损伤，而PAG则减弱了自噬损伤。H2S对AP过程中受损的自噬的调节作用进一步归因于自噬的过度激活，而不是自噬体与溶酶体的融合受到阻碍。为了阐明AP过程中H2S介导的自噬过度激活的分子机制，我们评估了AMP激活的蛋白激酶（AMPK）、AKT和哺乳动物雷帕霉素靶蛋白（mTOR）的磷酸化。此外，化合物C （CC）通过评估下游效应物的磷酸化，包括p70 S6激酶（P70S6k）和UNC‐51‐Like kinase 1 (ULK1)，来确定mTOR信号传导的参与。我们的研究结果表明，H2S通过激活AMPK和随后抑制mTOR来过度激活自噬，从而加剧了牛磺胆酸盐诱导的AP。因此，主动抑制H2S以恢复过度激活的自噬可能是一种很有希望的治疗AP相关损伤的方法。
Previously, we have shown that hydrogen sulphide (H2S) might be pro‐inflammatory during acute pancreatitis (AP) through inhibiting apoptosis and subsequently favouring a predominance of necrosis over apoptosis. In this study, we sought to investigate the detrimental effects of H2S during AP specifically with regard to its regulation on the impaired autophagy. The incubated levels of H2S were artificially intervened by an administration of sodium hydrosulphide (NaHS) or DL‐propargylglycine (PAG) after AP induction. Accumulation of autophagic vacuoles and pre‐mature activation of trypsinogen within acini, which indicate the impairment of autophagy during AP, were both exacerbated by treatment with NaHS but attenuated by treatment with PAG. The regulation that H2S exerted on the impaired autophagy during AP was further attributed to over‐activation of autophagy rather than hampered autophagosome–lysosome fusion. To elucidate the molecular mechanism that underlies H2S‐mediated over‐activation of autophagy during AP, we evaluated phosphorylations of AMP‐activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR). Furthermore, Compound C (CC) was introduced to determine the involvement of mTOR signalling by evaluating phosphorylations of downstream effecters including p70 S6 kinase (P70S6k) and UNC‐51‐Like kinase 1 (ULK1). Our findings suggested that H2S exacerbated taurocholate‐induced AP by over‐activating autophagy via activation of AMPK and subsequently, inhibition of mTOR. Thus, an active suppression of H2S to restore over‐activated autophagy might be a promising therapeutic approach against AP‐related injuries.
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影响因子：
7.3
作者：
Mustafa AK;Gadalla MM;Snyder SH
通讯作者：
Snyder SH
影响因子：
21.3
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影响因子：
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作者：
Choi AJ;Ryter SW
通讯作者：
Ryter SW
影响因子：
5.3
作者：
Li L;Fox B;Keeble J;Salto-Tellez M;Winyard PG;Wood ME;Moore PK;Whiteman M
通讯作者：
Whiteman M
影响因子：
15.9
作者：
Mareninova, Olga A.;Hermann, Kip;Gukovskaya, Anna S.
通讯作者：
Gukovskaya, Anna S.