细胞自噬与免疫系统的关系及其在乳腺癌免疫治疗中的应用

自噬是通过在溶酶体或液泡中降解破坏的蛋白或细胞器并再利用,实现真核细胞稳态、持续更新的保守进化过程。近年研究发现,自噬与免疫应答密切相关,且在乳腺肿瘤进展中发挥重要作用。文章综述了参与细胞自噬调控的复合物、细胞自噬与免疫系统关系、自噬在肿瘤中的作用、细胞自噬在乳腺癌免疫治疗中的应用,旨在为自噬与乳腺癌免疫治疗及临床疗效的相关研究及改善患者预后提供参考。     

电针预处理内关穴调控心肌缺血再灌注大鼠细胞自噬

目的观察电针预处理内关穴对心肌缺血再灌注大鼠细胞自噬的影响,阐明其作用及潜在机制。方法将50只大鼠随机分为5组:假手术组、模型组、电针组、抑制剂组和电针+抑制剂组。假手术组大鼠开胸后暴露心脏不做其他处理,模型组大鼠行在体心肌缺血再灌注术,电针组大鼠于造模前1周行电针内关穴治疗,抑制剂组大鼠于造模前1周注射磷脂酰肌醇3-激酶(PI3K)抑制剂渥曼青霉素,第8天行心肌缺血再灌注术,电针+抑制剂组同时进行电针和抑制剂预处理。治疗结束后处死取材,紫外分光光度法检测血清肌酸激酶同工酶(CK-MB)、诱导型一氧化氮合酶(iNOS)、血清总抗氧化能力(T-AOC)表达。石蜡切片免疫荧光检测自噬相关蛋白13抗体(ATG13)、哺乳动物雷帕霉素靶蛋白(mTOR)、PI3K在心肌细胞中的表达和定位。HE染色实验观察缺血再灌注大鼠心肌细胞中自噬引起的病理变化,透射电镜观察缺血再灌注大鼠心肌细胞超微结构变化。结果与假手术组相比,模型组大鼠血清中CK-MB和iNOS浓度显著增加,T-AOC浓度显著降低(P<0.05);与模型组相比,电针组、电针+抑制剂组和抑制剂组大鼠CK-MB和iNOS浓度降低,T-AOC浓度升高(P<0.05),其中以电针组的改变效果最显著。与假手术组比较,模型组、电针组、抑制剂组和电针+抑制剂组的mTOR、ATG13、PI3K在心肌细胞中的表达均升高;与模型组相比,电针组、抑制剂组和电针+抑制剂组的mTOR、ATG13、PI3K在心肌组织中的表达下降。HE染色结果显示:与假手术组比较,模型组心肌肌纤维出现溶解断裂甚至坏死,肿胀明显;电针组、抑制剂组及电针+抑制剂组心肌纤维间隙轻度增宽,坏死灶减轻,心肌细胞轻微肿胀,其中电针组变化最为明显。透射电镜观察结果显示:与假手术组相比,模型组心肌肌纤维出现溶解断裂甚至坏死,线粒体嵴不规则、缺失。电针组、抑制剂组及电针+抑制剂组心肌肌纤维间隙轻度增宽,细胞核及线粒体结构基本完整,其中以电针组变化最为明显。结论电针预处理可以促进自噬通量,通过促进自噬来减轻心肌缺血再灌注损伤,减少心肌细胞自噬体的形成,PI3K抑制剂渥曼青霉素可逆转这一保护作用。     

细胞自噬在牙周炎中的作用与机制

牙周炎是由牙菌斑生物膜引起的牙周组织的慢性炎症性疾病。细胞自噬是宿主对抗细菌感染的有效武器。近年来研究发现,细胞自噬不仅可以促进感染细胞对细菌和毒素的清除,而且有助于抑制炎症反应,以维持细胞内环境稳态,与牙周炎的发生发展关系密切。本文从细胞自噬与牙周病原菌感染的相互作用,细胞自噬与免疫炎症反应的相互调控,以及细胞自噬与牙槽骨代谢的关系3个方面,对细胞自噬与牙周炎发生发展的关系进行综述,为深入地研究细胞自噬与牙周炎相关机制提供参考,为牙周炎防治的研究提供新的思路。     

Hepatitis B virus x protein induces autophagy via activating death‐associated protein kinase

Hepatitis B virus x protein (HBX), a product of hepatitis B virus (HBV), is a multifunctional protein that regulates viral replication and various cellular functions. Recently, HBX has been shown to induce autophagy; however, the responsible mechanism is not fully known. In this study, we established stable HBX‐expressing epithelial Chang cells as the platform to study how HBX induced autophagy. The results showed that the overexpression of HBX resulted in starvation‐induced autophagy. HBX‐induced autophagy was related to its ability to dephosphorylate/activate death‐associated protein kinase (DAPK). The block of DAPK by its siRNA significantly counteracted HBX‐mediated autophagy, confirming the positive role of DAPK in this process. HBX also induced Beclin 1, which functions at the downstream of the DAPK‐mediated autophagy pathway. Although HBX could activate JNK, a kinase known to participate in autophagy in certain conditions, the change in JNK failed to influence HBX‐induced autophagy. In conclusion, HBX induces autophagy via activating DAPK in a pathway related to Beclin 1, but not JNK. This new finding should help us to understand the role of autophagy in HBX‐mediated pathogenesis and thus may provide targets for intervening HBX‐related disorders.     

间歇低氧对大鼠海马神经细胞自噬相关蛋白表达的影响

目的通过模拟阻塞性睡眠呼吸暂停低通气综合征的发病特征,建立大鼠间歇性低氧(IH)模型,观察IH后大鼠海马CA1区神经细胞线粒体自噬及相关蛋白的表达。方法 72只雄性Wistar大鼠随机分为对照组36只和间歇低氧(5%IH)组36只,对照组向低氧箱内持续注入压缩空气,5%IH组每天放入低氧箱内IH暴露7h,模型完成后分别于1、3、5、7、10和14d采用透射电镜观察大鼠海马CA1区神经细胞线粒体超微结构的改变;免疫组织化学法检测Beclin-1和微管相关蛋白1轻链3(LC3)的表达。结果与对照组比较,5%IH组3d开始出现线粒体超微结构的明显改变,可见线粒体自噬体形成;1、3、5、10和14dBeclin-1及LC3蛋白表达均明显升高(P<0.05),于10d达高峰(P<0.05),14d开始下降,差异有统计学意义(P<0.05)。结论 IH早期可诱导大鼠海马神经细胞线粒体发生自噬及自噬相关蛋白Beclin-1和LC3的表达。     

BDNF-TrkB pathway mediates antidepressant-like roles of H2S in diabetic rats via promoting hippocampal autophagy

Hydrogen sulfide (H₂S) plays antidepressant-like roles in diabetic rats. However, the underlying mechanisms remain unclear. Brain-derived neurotropic factor (BDNF), a neurotrophic factor, plays important regulatory roles in depression by its high-affinity tropomysin-related kinase B (TrkB) receptor. Autophagy also is implicated in modulation of depression. Previous work confirmed the modulatory roles of H₂S in BDNF protein expression and autophagy. Thus, in this study, we explored whether the BDNF-TrkB pathway mediates the antidepressant-like effects of H₂S in diabetic rats and whether this process is achieved via promoting hippocampal autophagy. We demonstrated that H₂S upregulated the expressions of BDNF and p-TrkB proteins in the hippocampus of streptozotocin (STZ)-induced diabetic rats. K252a (an inhibitor of BDNF-TrkB pathway) reversed the antidepressant-like roles of H₂S, as evidenced by the tail suspension, forced swimming, novelty suppressed feeding, and elevated plus-maze tests. Furthermore, K252a abolished H₂S-promoted hippocampal autophagy in diabetic rats, as evidenced by a decrease in the number of autolysosome, downregulation of Beclin-1 (a regulator of autophagy in the early stage of the formation of autophagosomal membranes and its level is positively correlated with autophagic activity) expression, and upregulation of P62 (a substrate of autophagic degradation and its level is inversely correlated with autophagic activity) expression, in the hippocampus of rats co-treated with NaHS and STZ. Taken together, these data indicated that the BDNF-TrkB pathway mediates the antidepressant-like roles of H₂S in diabetic rats by enhancing hippocampal autophagy.     

Long non-coding RNA UCA1 promotes autophagy by targeting miR-96-5p in acute myeloid leukaemia

Long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been identified as an oncogene and is involved in acute myeloid leukaemia (AML). Autophagy contributes to tumourigenesis and cancer cell survival. The purpose of this study was to investigate the regulatory role and mechanism of UCA1 in AML cell viability by its effect on autophagy. The expression of UCA1, miR-96-5p, and ATG7 was determined by qRT-PCR and western blot. Cell proliferation was examined by MTT assay. The autophagy level was assessed by green fluorescent protein (GFP)-LC3 immunofluorescence and western blot. The interaction between UCA1 and miR-96-5p or ATG7 was analyzed by luciferase reporter activity. The results showed that UCA1 promoted AML cell proliferation by inducing autophagy. Mechanistically, UCA1 acted as a sponge of miR-96-5p by binding to miR-96-5p. ATG7 was a direct target of miR-96-5p and positively regulated by UCA1. Further results showed that the miR-96-5p mimic effectively counteracted the UCA1 overexpression-mediated induction of the ATG7/autophagy pathway. Collectively, UCA1 functions as a sponge of miR-96-5p to upregulate its target ATG7, thereby resulting in autophagy induction. Our findings reveal a UCA1-mediated molecular mechanism responsible for autophagy induction in AML and help to improve the understanding of the molecular mechanism of AML progression.