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1.
杨海玉 《国际病理科学与临床杂志》2016,(3):327-330
坏死性凋亡是新近发现的一种程序性坏死途径,在死亡受体信号激活后由RIP1和RIP3调控,并可被化合物necrostatin-1特异性抑制。目前研究证实坏死性凋亡涉及多种中枢神经系统损伤疾病的发生机制,并且通过干预坏死性凋亡信号通路,对诸多因素引起的中枢神经系统损伤具有一定的保护作用。深入研究坏死性凋亡的分子调控机制,有望为中枢神经系统损伤疾病治疗提供更多的潜在新靶点。 相似文献
2.
BAX and BCL‐2 polymorphisms,as predictors of proliferative vitreoretinopathy development in patients suffering retinal detachment: the Retina 4 project 下载免费PDF全文
Salvador Pastor‐Idoate Irene Rodríguez‐Hernández Jimena Rojas Itziar Fernández María‐Teresa García‐Gutierrez Jose M. Ruiz‐Moreno Amandio Rocha‐Sousa Yashin D. Ramkissoon Steven Harsum Robert E. MacLaren David G. Charteris Jan C. Van Meurs Rogelio González‐Sarmiento Jose C. Pastor the Genetics on PVR Study Group 《Acta ophthalmologica. Supplement》2015,93(7):e541-e549
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目的:探讨感染性眼内炎患者玻璃体液中坏死性凋亡相关蛋白 MCP-1的表达及其与视力预后的关系,为预测疾病预后及进一步的眼内药物干预,保护视功能提供实验室依据。方法收集17例感染性眼内炎患者的玻璃体液,检测坏死性凋亡相关蛋白单核细胞趋化蛋白1(MCP-1)的表达,分析临床治疗效果。结果实验组感染性眼内炎患者玻璃体液中 MCP-1的浓度显著高于对照组 MCP-1的浓度(P <0.05);实验组的 MCP-1浓度与最佳矫正视力呈负相关性(P<0.05)。结论感染性眼内炎患者眼内有坏死性凋亡的发生,与患者视功能损害有关,这为进一步干预坏死性凋亡,保护患者视功能提供了依据。 相似文献
5.
Xialian Wu Yeyang Ma Kun Zhao Jing Zhang Yunpeng Sun Yichen Li Xingqi Dong Hong Hu Jing Liu Jian Wang Xia Zhang Bing Li Huayi Wang Dan Li Bo Sun Junxia Lu Cong Liu 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(14)
Receptor-interacting protein kinases 3 (RIPK3), a central node in necroptosis, polymerizes in response to the upstream signals and then activates its downstream mediator to induce cell death. The active polymeric form of RIPK3 has been indicated as the form of amyloid fibrils assembled via its RIP homotypic interaction motif (RHIM). In this study, we combine cryogenic electron microscopy and solid-state NMR to determine the amyloid fibril structure of RIPK3 RHIM-containing C-terminal domain (CTD). The structure reveals a single protofilament composed of the RHIM domain. RHIM forms three β-strands (referred to as strands 1 through 3) folding into an S shape, a distinct fold from that in complex with RIPK1. The consensus tetrapeptide VQVG of RHIM forms strand 2, which zips up strands 1 and 3 via heterozipper-like interfaces. Notably, the RIPK3-CTD fibril, as a physiological fibril, exhibits distinctive assembly compared with pathological fibrils. It has an exceptionally small fibril core and twists in both handedness with the smallest pitch known so far. These traits may contribute to a favorable spatial arrangement of RIPK3 kinase domain for efficient phosphorylation.Necroptosis is an important form of regulated necrotic cell death, dysregulation of which is closely associated with a variety of human diseases, including neurodegenerative diseases (1, 2), inflammatory disorders (3–5), and cancers (6, 7). RIPK3 (receptor-interacting protein kinase 3) serves as the central node to converge multiple upstream signals to induce necroptosis (8–11). RIPK3 is activated via interactions with proteins that contain the RIP homotypic interaction motif (RHIM) such as RIPK1 (receptor-interacting protein kinase 1), TRIF (TIR-domain-containing adapter-inducing interferon-β), and ZBP1/DAI (Z-DNA-binding protein 1/DNA-dependent activator of IFN-regulatory factors). RIPK1 mediates RIPK3 activation downstream of death receptors, such as TNFR1 (12). TRIF links RIPK3 to the TLR3 and TLR4 signaling pathway (8). ZBP1/DAI mediates RIPK3 activation in response to certain viruses, such as influenza A virus (9, 10). RIPK3 is composed of a well-defined N-terminal kinase domain and a RHIM-containing C-terminal domain (CTD) (13). Previous studies show that RHIM plays an important role in the interactions of RIPK3 with its upstream mediators and amyloid fibrillation of RIPK3 (9, 10, 14, 15). A previous solid-state NMR (ssNMR) study has revealed the structure of a heterofibril core formed by the CTDs of RIPK3 and RIPK1, where the RHIM domains of both proteins adopt a serpentine fold and stack alternatively along the fibril axis (15). The structure provides insights into how RIPK1 recruits and activates RIPK3 for signaling transduction. However, it remains unknown how RIPK3 assemblies into fibril in the absence of RIPK1.In this work, by using cryo-EM and ssNMR, we determined the structures of two amyloid fibrils formed by RIPK3-CTD. Despite the different fibril preparation, the RIPK3-CTD fibrils present a nearly identical structure. The fibril core exhibits an exceptionally small S-shaped fold of RHIM, which is distinct from that in the heterofibril of RIPK1 and RIPK3 CTDs. The consensus tetrapeptide VQVG forms the central strand 2 of the S-shaped structure and forms heterosteric zipper interfaces with the adjacent strands 1 and 2 within the same subunit. Intriguingly, the RIPK3-CTD fibril presents in both left and right handedness and features a minimum fibril core among the 50 different cryo-EM fibril structures reported previously and also represents the smallest fibril pitch and largest twist angle. By analyzing the reported cryo-EM fibril structures, we observed a strong positive correlation between the size of fibril core and the fibril pitch. Furthermore, we discussed how the small RIPK3 fibril core leads to a highly twisted fibril, which may display the N-terminal kinase domains in a favorable geometry to increase the efficiency of RIPK3 phosphorylation. 相似文献
6.
A. Lau S. Wang J. Jiang A. Haig A. Pavlosky A. Linkermann A. M. Jevnikar 《American journal of transplantation》2013,13(11):2805-2818
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ZBP1 has been characterized as a critical innate immune sensor of not only viral RNA products but also endogenous nucleic acid ligands. ZBP1 sensing of the Z-RNA produced during influenza virus infection induces cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). PANoptosis is a coordinated cell death pathway that is driven through a multiprotein complex called the PANoptosome and enables crosstalk and co-regulation among these processes. During influenza virus infection, a key step in PANoptosis and PANoptosome assembly is the formation of the ZBP1-NLRP3 inflammasome. When Z-RNA is sensed, ZBP1 recruits RIPK3 and caspase-8 to activate the ZBP1-NLRP3 inflammasome. Several other host factors have been found to be important for ZBP1-NLRP3 inflammasome assembly, including molecules involved in the type I interferon signaling pathway and caspase-6. Additionally, influenza viral proteins, such as M2, NS1, and PB1-F2, have also been shown to regulate the ZBP1-NLRP3 inflammasome. This review explains the functions of ZBP1 and the mechanistic details underlying the activation of the ZBP1-NLRP3 inflammasome and the formation of the PANoptosome. Improved understanding of the ZBP1-NLRP3 inflammasome will direct the development of therapeutic strategies to target infectious and inflammatory diseases. 相似文献
8.
Diana G. Bohannon Yueying Wang Colin H. Reinhart Julian B. Hattler Jiangtao Luo Hamid R. Okhravi Jianshui Zhang Qingsheng Li Marcelo J. Kuroda Jayoung Kim Woong‐Ki Kim 《Brain pathology (Zurich, Switzerland)》2020,30(3):603-613
We previously showed that rhesus macaques neonatally infected with simian immunodeficiency virus (SIV) do not develop SIV encephalitis (SIVE) and maintain low brain viral loads despite having similar plasma viral loads compared to SIV‐infected adults. We hypothesize that differences in myeloid cell populations that are the known target of SIV and HIV in the brain contribute to the lack of neonatal susceptibility to lentivirus‐induced encephalitis. Using immunohistochemistry and immunofluorescence microscopy, we examined the frontal cortices from uninfected and SIV‐infected infant and adult macaques (n = 8/ea) as well as adults with SIVE (n = 4) to determine differences in myeloid cell populations. The number of CD206+ brain perivascular macrophages (PVMs) was significantly greater in uninfected infants than in uninfected adults and was markedly lower in SIV‐infected infants while microglia numbers were unchanged across groups. CD206+ PVMs, which proliferate after infection in SIV‐infected adults, did not undergo proliferation in infants. While virtually all CD206+ cells in adults are also CD163+, infants have a distinct CD206 single‐positive population in addition to the double‐positive population commonly seen in adults. Notably, we found that more than 60% of these unique CD206+CD163? PVMs in SIV‐infected infants were positive for cleaved caspase‐3, an indicator of apoptosis, and that nearly 100% of this subset were concomitantly positive for the necroptosis marker receptor‐interacting protein kinase‐3 (RIP3). These findings show that distinct subpopulations of PVMs found in infants undergo programmed cell death instead of proliferation following SIV infection, which may lead to the absence of PVM‐dependent SIVE and the limited size of the virus reservoir in the infant brain. 相似文献
9.
Hydrogen peroxide induces programmed necrosis in rat nucleus pulposus cells through the RIP1/RIP3‐PARP‐AIF pathway 下载免费PDF全文
Lei Zhao Hui Lin Songfeng Chen Sheng Chen Min Cui Deyao Shi Baichuan Wang Kaige Ma Zengwu Shao 《Journal of orthopaedic research》2018,36(4):1269-1282
10.
Trichonas G Murakami Y Thanos A Morizane Y Kayama M Debouck CM Hisatomi T Miller JW Vavvas DG 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(50):21695-21700
Apoptosis has been shown to be a significant form of cell loss in many diseases. Detachment of photoreceptors from the retinal pigment epithelium, as seen in various retinal disorders, causes photoreceptor loss and subsequent vision decline. Although caspase-dependent apoptotic pathways are activated after retinal detachment, caspase inhibition by the pan-caspase inhibitor Z-VAD fails to prevent photoreceptor death; thus, we investigated other pathways leading to cell loss. Here, we show that receptor interacting protein (RIP) kinase-mediated necrosis is a significant mode of photoreceptor cell loss in an experimental model of retinal detachment and when caspases are inhibited, RIP-mediated necrosis becomes the predominant form of death. RIP3 expression, a key activator of RIP1 kinase, increased more than 10-fold after retinal detachment. Morphological assessment of detached retinas treated with Z-VAD showed decreased apoptosis but significantly increased necrotic photoreceptor death. RIP1 kinase inhibitor necrostatin-1 or Rip3 deficiency substantially prevented those necrotic changes and reduced oxidative stress and mitochondrial release of apoptosis-inducing factor. Thus, RIP kinase-mediated programmed necrosis is a redundant mechanism of photoreceptor death in addition to apoptosis, and simultaneous inhibition of RIP kinases and caspases is essential for effective neuroprotection and may be a novel therapeutic strategy for treatment of retinal disorders. 相似文献