Crosstalk of liver immune cells and cell death mechanisms in different murine models of liver injury and its clinical relevance

BACKGROUND： Liver inflammation or hepatitis is a result of pluripotent interactions of cell death molecules, cytokines, chemokines and the resident immune cells collectively called as microenvironment. The interplay of these inflammatory mediators and switching of immune responses during hepatotoxic, viral, drug-induced and immune cell-mediated hepatitis decide the fate of liver pathology. The present review aimed to describe the mechanisms of liver injury, its relevance to human liver pathology and insights for the future therapeutic interventions.DATA SOURCES： The data of mouse hepatic models and rele- vant human liver diseases presented in this review are system- atically collected from PubMed, ScienceDirect and the Web of Science databases published in English. RESULTS： The hepatotoxic liver injury in mice induced by the metabolites of CC14, acetaminophen or alcohol represent ne- crotic cell death with activation of cytochrome pathway, for- mation of reactive oxygen species （ROS） and mitochondrial damage. The Fas or TNF-a induced apoptotic liver injury was dependent on activation of caspases, release of cytochrome c and apoptosome formation. The ConA-hepatitis demonstrat- ed the involvement of TRAIL-dependent necrotic/necroptotic cell death with activation of RIPK1/3. The a-GalCer-induced liver injury was mediated by TNF-a. The LPS-induced hepatitis involved TNF-a, Fas/FasL, and perforin/granzyme cell death pathways. The MHV3 or Poly（I：C） induced liver injury was mediated by natural killer cells and TNF-a signaling. The necrotic ischemia-reperfusion liver injury was mediated by hypoxia, ROS, and pro-inflammatory cytokines; however, necroptotic cell death was found in partial hepatectomy. The crucial role of immune ceils and cell death mediators in viral hepatitis （HBV, HCV）, drug-induced liver injury, non-alcohol- ic fatty liver disease and alcoholic liver disease in human were discussed. CONCLUSIONS： The mouse animal models of hepatitis provide a parallel approach for the study of human liver pathology. Blocking or stimulating the pathways associated with liver cell death could unveil the novel therapeutic strategies in the management of liver diseases.

Cell-death-mode switch from necrosis to apoptosis in hydrogen peroxide treated macrophages

Cell death is typically defined either as apoptosis or necrosis. Because the consequences of apoptosis and necrosis are quite different for an entire organism, the investigation of the cell-death-mode switch has considerable clinical significance. The existence of a necrosis-to-apoptosis switch induced by hydrogen peroxide in macrophage cell line RAW 264.7 cells was confirmed by using flow cytometry and fluorescence microscopy. With the help of computational simulations, this study predicted that negative feedbacks between NF-κB and MAPKs are implicated in converting necrosis into apoptosis in macrophages exposed to hydrogen peroxide, which has significant implications.

中子和γ射线照射对小鼠骨髓造血细胞死亡方式的探讨(英文)

为探讨中子和γ射线照射后小鼠骨髓造血细胞的死亡方式及其意义,采用不同剂量中子和60Coγ射线全身照射350只BALB/c小鼠,通过光镜、电镜、流式细胞术、原位末端标记和DNA凝胶电泳等观察造血细胞凋亡与坏死情况。研究发现,中子照射后小鼠骨髓中坏死和凋亡的造血细胞均明显增多,5.5Gy组以坏死为主,而γ射线照射后则以凋亡为主,且呈剂量相关性。凋亡的细胞表现为核染色质浓缩、边移,呈半月型、环状或不规则状,凋亡小体形成,电泳下见DNA梯状图谱。坏死的细胞表现为核肿胀、溶解,线粒体膜、核膜等膜性结构破坏。2.5～5.5Gy中子及5.5～12Gyγ射线照射可使骨髓造血细胞死亡方式不同:中子照射以凋亡与坏死并存,5.5Gy组以坏死为主;而γ射线照射则以凋亡为主。

细胞胀亡及其研究进展

胀亡作为不同于凋亡的另一种细胞死亡形式,已成为近年形态学研究的热点。本文依据文献资料从细胞胀亡的概念、形态学特征、发生机制及检测方法等方面进行了综述。随着对胀亡研究的深入,将对法医学科研及实践产生深远的影响。

子宫内膜异位症不同分期患者内膜组织异常表达基因及相关细胞死亡方式分析

目的探讨子宫内膜异位症不同分期患者子宫内膜组织异常基因表达情况,并挖掘最相关细胞死亡途径。方法检索美国国立生物技术信息中心(NCBI)的GEO(Gene Expression Omnibus)数据库子宫内膜异位症患者子宫内膜组织表达谱芯片,通过GEO2R工具筛选差异基因,并利用DAVID数据库进行生物学过程通路富集分析,将差异基因与GeneCards检索得到的五种细胞死亡相关基因交集分析,以判别最高相关性的细胞死亡方式。结果最终纳入一项子宫内膜异位症患者子宫内膜组织表达谱芯片数据,共涉及111例子宫内膜组织样本。筛选出子宫内膜异位症疾病相关异常表达基因431个(|logFC|>2.5,调整后P值<0.05),在RNA聚合酶II启动子转录的正调控、细胞增殖、细胞分裂、凋亡过程正调控和细胞内信号转导等60条通路显著富集(P<0.05)。IFI6等14种基因在微轻度与中重度子宫内膜异位症患者内膜组织存在显著表达差异(调整后P值<0.05)。在五种细胞死亡方式中,凋亡与子宫内膜异位症患者子宫内膜组织细胞最为相关,共有1058个交集基因。结论子宫内膜异位症患者子宫内膜组织基因表达存在显著异常,与凋亡相关基因关联密切,不同分期的子宫内膜异位症患者也许能够通过子宫内膜组织基因表达差异进行区分。

Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications

Cancer is the leading cause of death worldwide. Drugs play a pivotal role in cancer treatment, but the complex biological processes of cancer cells seriously limit the efficacy of various anticancer drugs. Autophagy, a self-degradative system that maintains cellular homeostasis, universally operates under normal and stress conditions in cancer cells. The roles of autophagy in cancer treatment are still controversial because both stimulation and inhibition of autophagy have been reported to enhance the effects of anticancer drugs. Thus, the important question arises as to whether we should try to strengthen or suppress autophagy during cancer therapy. Currently, autophagy can be divided into four main forms according to its different functions during cancer treatment: cytoprotective(cell survival), cytotoxic(cell death), cytostatic(growth arrest), and nonprotective(no contribution to cell death or survival). In addition, various cell death modes, such as apoptosis, necrosis, ferroptosis, senescence, and mitotic catastrophe, all contribute to the anticancer effects of drugs. The interaction between autophagy and these cell death modes is complex and can lead to anticancer drugs having different or even completely opposite effects on treatment. Therefore, it is important to understand the underlying contexts in which autophagy inhibition or activation will be beneficial or detrimental.That is, appropriate therapeutic strategies should be adopted in light of the different functions of autophagy. This review provides an overview of recent insights into the evolving relationship between autophagy and cancer treatment.

中子和γ射线照射对小鼠骨髓造血细胞死亡方式的探讨

目的 探讨中子和γ射线照射后小鼠骨髓造血细胞的死亡方式及其意义。方法 采用不同剂量中子和6 0 Coγ射线全身照射 35 0只BALB/c小鼠 ,通过光镜、电镜、流式细胞术、原位末端标记和DNA凝胶电泳等观察造血细胞凋亡与坏死情况。结果 中子照射后小鼠骨髓中坏死和凋亡的造血细胞均明显增多 ,5 5Gy组以坏死为主 ;而γ射线照射后则以凋亡为主 ,且呈剂量相关性。凋亡的细胞表现为核染色质浓缩、边移 ,呈半月型、环状或不规则状 ,凋亡小体形成 ,电泳下见DNA梯状图谱。坏死的细胞表现为核肿胀、溶解 ,线粒体膜、核膜等膜性结构破坏。结论 2 5～ 5 5Gy中子及 5 5～ 12Gyγ射线照射可使骨髓造血细胞死亡方式不同 :中子照射见凋亡与坏死并存 ,5 5Gy组以坏死为主 ;而γ射线照射则以凋亡为主。