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Piotr T Filipczak, Cynthia L Thomas, Wenshu Chen, Andrew Salzman, Jacob D McDonald, Yong Lin, Steven A Belinsky
Tuberous sclerosis complex (TSC) is a genetic multi-organ disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in hyperactivation of mTOR- and Raf/MEK/MAPK-dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach...
October 18, 2016: Cancer Research
C-Y Lin, T-W Chang, W-H Hsieh, M-C Hung, I-H Lin, S-C Lai, Y-J Tzeng
Tanshinone IIA (Tan IIA), a constituent of the traditional medicinal plant Salvia miltiorrhiza BUNGE, has been reported to possess anticancer activity through induction of apoptosis in many cancer cells. Surprisingly, the present study finds that Tan IIA simultaneously causes apoptosis and necroptosis in human hepatocellular carcinoma HepG2 cells. We further find that apoptosis can be converted to necroptosis by pan-caspase inhibitor Z-VAD-fmk, and the two death modes can be blocked by necroptotic inhibitor necrostatin-1...
2016: Cell Death Discovery
J Xin, D You, P Breslin, J Li, J Zhang, W Wei, J Cannova, A Volk, R Gutierrez, Y Xiao, A Ni, G Ng, R Schmidt, Z Xia, J Pan, H Chen, M M Patel, P C Kuo, S Nand, A R Kini, J Zhang, J Chen, J Zhu, J Zhang
Tumor necrosis factor-α (TNF)-induced RIP1/RIP3-mediated necroptosis has been proposed to be an alternative strategy for treating apoptosis-resistant leukemia. However, we found that most acute myeloid leukemia (AML) cells, especially M4 and M5 subtypes, produce TNF and show basal level activation of RIP1/RIP3/MLKL signaling, yet do not undergo necroptosis. TNF, through RIP1/RIP3 signaling, prevents degradation of SOCS1, a key negative regulator of interferon-γ (IFN-γ) signaling. Using both pharmacologic and genetic assays, we show here that inactivation of RIP1/RIP3 resulted in reduction of SOCS1 protein levels and partial differentiation of AML cells...
October 17, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Xing Lin, Qianshun Chen, Chen Huang, Xunyu Xu
Lung cancer is one of the most common cancers in the world. Cylindromatosis (CYLD) is a deubiquitination enzyme and contributes to the degradation of ubiquitin chains on RIP1. The aim of the present study is to investigate the levels of CYLD in lung cancer patients and explore the molecular mechanism of CYLD in the lung cancer pathogenesis. The levels of CYLD were detected in human lung cancer tissues and the paired paracarcinoma tissues by real-time PCR and western blotting analysis. The proliferation of human lung cancer cells was determined by MTT assay...
2016: Mediators of Inflammation
Chengcheng Yang, Huangzhen Wang, Boxiang Zhang, Yimeng Chen, Yamin Zhang, Xin Sun, Guodong Xiao, Kejun Nan, Hong Ren, Sida Qin
BACKGROUND: LCL161, a novel Smac mimetic, is known to have anti-tumor activity and improve chemosensitivity in various cancers. However, the function and mechanisms of the combination of LCL161 and paclitaxel in non-small cell lung cancer (NSCLC) remain unknown. METHODS: Cellular inhibitor of apoptotic protein 1 and 2 (cIAP1&2) expression in NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry. The correlations between cIAP1&2 expression and clinicopathological characteristics, prognosis were analyzed...
September 30, 2016: Journal of Experimental & Clinical Cancer Research: CR
Cho Rong Kim, Jie Hyun Kim, Hae-Young Lopilly Park, Chan Kee Park
PURPOSE: A recent study revealed a novel form of cell death, termed necroptosis, or programmed necrosis. Previous research indicated that after ischemia-reperfusion (IR) injury to the retina, Tumor Necrosis Factor α (TNFα) is increased, which may activate necroptosis. This study observed macroglial cell activation, and in particular, astrocyte activation, after the release of TNFα and other necroptosis factors in the rat retina due to IR. MATERIALS AND METHODS: IR was induced in the retinas of adult male Sprague-Dawley rats by increasing the intraocular pressure to 160 mmHg and then allowing reperfusion...
October 12, 2016: Current Eye Research
Hongwang Cui, Yongjun Zhu, Qiming Yang, Weikang Zhao, Shiyang Zhang, Ao Zhou, Dianming Jiang
Estrogen (E2) deficiency has been associated with accelerated osteocyte apoptosis. Our previous study showed necroptosis accelerated the loss of osteocytes in E2 deficiency-induced osteoporosis in rats in addition to apoptosis, but the mechanism involved remains. Necroptosis is a caspase-independent form of programmed cell death. In the necroptosis pathway, receptor interaction proteins 1 and 3 (RIP1/3) play vital roles. Necrostatin-1 (Nec-1) has been confirmed to be a specific inhibitor of necroptosis. However, the effect of Nec-1 on postmenopausal osteoporosis remains ambiguous...
October 5, 2016: Scientific Reports
Cong Wang, Bowen Yao, Meng Xu, Xin Zheng
Although growing body of evidences have identified a critical role for receptor-interacting protein kinase 1 (RIP1) in mediating cell death signaling, its possible contribution to hepatocellular carcinoma (HCC) progression remains unclear. Here, we displayed that expression of RIP1 was significantly upregulated in HCC tissues than in adjacent liver tissues from 81.9 % HCC patients (P < 0.001) by immunohistochemistry (IHC) staining. Overexpression of RIP1 was found positively associated with HBV infection, advanced TNM staging, portal vein invasion, and intrahepatic metastases...
October 4, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Nina Tang, Juan Ma, Ke Si Wang, Chunliu Mi, Ying Lv, Lian Xun Piao, Guang Hua Xu, Xuezheng Li, Jung Joon Lee, Xuejun Jin
Nuclear factor-kappa B (NF-κB) has been reported to play a pivotal role in many physiological processes including inflammation, apoptosis, and angiogenesis. We discovered a potent natural NF-κB inhibitor, dihydromyricetin, from the traditional herb Ampelopsis grossedentata, which has a long history of use in food and medicine. In this study, we demonstrated the effect of dihydromyricetin on NF-κB activation in TNF-α-induced HeLa cells. Dihydromyricetin was found to markedly inhibit the phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα), and subsequent nuclear translocation of p65...
November 2016: Molecular and Cellular Biochemistry
Marta B Afonso, Pedro M Rodrigues, André L Simão, Dimitry Ofengeim, Tânia Carvalho, Joana D Amaral, Maria M Gaspar, Helena Cortez-Pinto, Rui E Castro, Junying Yuan, Cecília M P Rodrigues
Cholestasis encompasses liver injury and inflammation. Necroptosis, a necrotic cell death pathway regulated by receptor-interacting protein (RIP) 3, may mediate cell death and inflammation in the liver. We aimed to investigate the role of necroptosis in mediating deleterious processes associated with cholestatic liver disease. Hallmarks of necroptosis were evaluated in liver biopsies of primary biliary cholangitis (PBC) patients and in wild-type and RIP3-deficient (RIP3(-/-)) mice subjected to common bile duct ligation (BDL)...
2016: Cell Death & Disease
Xiaoyun Guo, Haifeng Yin, Yi Chen, Lei Li, Jing Li, Qinghang Liu
Necroptosis has emerged as a new form of programmed cell death implicated in a number of pathological conditions such as ischemic injury, neurodegenerative disease, and viral infection. Recent studies indicate that TGFβ-activated kinase 1 (TAK1) is nodal regulator of necroptotic cell death, although the underlying molecular regulatory mechanisms are not well defined. Here we reported that TAK1 regulates necroptotic signaling as well as caspase 8-mediated apoptotic signaling through both NFκB-dependent and -independent mechanisms...
2016: Cell Death & Disease
John P Dowling, Yubo Cai, John Bertin, Peter J Gough, Jianke Zhang
The death receptor, Fas, triggers apoptotic death and is essential for maintaining homeostasis in the peripheral lymphoid organs. RIP1 was originally cloned when searching for Fas-binding proteins and was later shown to associate also with the signaling complex of TNFR1. Although Fas exclusively induces apoptosis, TNFR1 primarily activates the pro-survival/pro-inflammatory NF-κB pathway. Mutations in Fas lead to lymphoproliferative (lpr) diseases, and deletion of TNFR1 results in defective innate immune responses...
2016: Cell Death & Disease
Shihong Wen, Yihong Ling, Wenjing Yang, Jiantong Shen, Cai Li, Wentao Deng, Weifeng Liu, Kexuan Liu
Cell death is an important biological process that is believed to have a central role in intestinal ischaemia/reperfusion (I/R) injury. While the apoptosis inhibition is pivotal in preventing intestinal I/R, how necrotic cell death is regulated remains unknown. Necroptosis represents a newly discovered form of programmed cell death that combines the features of both apoptosis and necrosis, and it has been implicated in the development of a range of inflammatory diseases. Here, we show that receptor-interacting protein 1/3 (RIP1/3) kinase and mixed lineage kinase domain-like protein recruitment mediates necroptosis in a rat model of ischaemic intestinal injury in vivo...
September 28, 2016: Journal of Cellular and Molecular Medicine
Farinoosh Fakharnia, Fariba Khodagholi, Leila Dargahi, Abolhassan Ahmadiani
The mitochondrial permeability transition pore (mPTP) is a complex channel of the inner membrane, the opening of which leads to mitochondrial swelling and dissipation of mitochondrial membrane potential (MMP). Here, we aimed to evaluate the role of the cyclophilin D (CypD) as a prominent mediator of mPTP, on necroptosis and autophagy as well as apoptosis, beyond the global cerebral ischemia-reperfusion (I/R) injury. We showed that while cerebral I/R injury is accompanied by loss of MMP, mitochondrial swelling and programmed cell death, pretreatment with cyclosporine-A (CsA) as a potent inhibitor of CypD, led to partial but significant reduction in necroptosis markers, RIP1 and RIP3 as well as activity of glutamate-ammonia ligase (GLUL) and glutamate dehydrogenase 1 (GLUD1), downstream enzymes of RIP3...
September 23, 2016: Journal of Molecular Neuroscience: MN
Zhirui Zhang, Hong-Mei Li, Can Zhou, Qixiang Li, Linyan Ma, Zixuan Zhang, Yiming Sun, Lirong Wang, Xudong Zhang, Bing Zhu, Young-Soo Hong, Cheng-Zhu Wu, Hao Liu
BACKGROUND: Hsp90 proteins are important therapeutic targets for many anti-cancer drugs in clinical trials. Geldanamycin (GA) was identified as the first natural inhibitor of Hsp90, increasing evidence suggests that GA was not a good choice for clinical trials. In this study, we investigated two new non-benzoquinone geldanamycin analogs of Hsp90 inhibitors, DHQ3 and 17-demethoxy-reblastatin (17-DR), to explore the molecular mechanisms of their anti-cancer activity in vivo and vitro. METHODS: MTT and colony formation assays were used to measure cell viability...
2016: Journal of Experimental & Clinical Cancer Research: CR
Ying Mao, Xigui Chen, Min Xu, Kyota Fujita, Kazumi Motoki, Toshikazu Sasabe, Hidenori Homma, Miho Murata, Kazuhiko Tagawa, Takuya Tamura, Julia Kaye, Steven Finkbeiner, Giovanni Blandino, Marius Sudol, Hitoshi Okazawa
Neuronal cell death in neurodegenerative diseases is not fully understood. Here we report that mutant huntingtin (Htt), a causative gene product of Huntington's diseases (HD) selectively induces a new form of necrotic cell death, in which endoplasmic reticulum (ER) enlarges and cell body asymmetrically balloons and finally ruptures. Pharmacological and genetic analyses revealed that the necrotic cell death is distinct from the RIP1/3 pathway-dependent necroptosis, but mediated by functional deficiency of TEAD/YAP-dependent transcription...
September 12, 2016: Human Molecular Genetics
Kate Welsh, Snezana Milutinovic, Robert J Ardecky, Marcos Gonzalez-Lopez, Santhi Reddy Ganji, Peter Teriete, Darren Finlay, Stefan Riedl, Shu-Ichi Matsuzawa, Clemencia Pinilla, Richard Houghten, Kristiina Vuori, John C Reed, Nicholas D P Cosford
Members of the Inhibitor of APoptosis (IAP) protein family suppress apoptosis within tumor cells, particularly in the context of immune cell-mediated killing by the tumor necrosis factor (TNF) superfamily cytokines. Most IAPs are opposed endogenously by the second mitochondrial activator of caspases (SMAC), which binds to selected baculovirus IAP repeat (BIR) domains of IAPs to displace interacting proteins. The development of SMAC mimetics as novel anticancer drugs has gained impetus, with several agents now in human clinical trials...
2016: PloS One
Hong-Min Ni, Mitchell R McGill, Xiaojuan Chao, Benjamin L Woolbright, Hartmut Jaeschke, Wen-Xing Ding
How different cell death modes and cell survival pathways cross talk remains elusive. We determined the interrelation of apoptosis, necrosis, and autophagy in tumor necrosis factor (TNF)-α/actinomycin D (ActD) and lipopolysaccharide/D-galactosamine (GalN)-induced hepatotoxicity in vitro and in vivo. We found that TNF-α/ActD-induced apoptosis was completely blocked by a general caspase inhibitor ZVAD-fmk at 24 hours but hepatocytes still died by necrosis at 48 hours. Inhibition of caspases also protected mice against lipopolysaccharide/GalN-induced apoptosis and liver injury at the early time point, but this protection was diminished after prolonged treatment by switching apoptosis to necrosis...
October 2016: American Journal of Pathology
Sebastian Bittner, Gertrud Knoll, Martin Ehrenschwender
Death receptor 3 (DR3) was initially identified as a T cell co-stimulatory and pro-inflammatory molecule, but further studies revealed a more complex role of DR3 and its ligand TL1A. Although being a death receptor, DR3 gained to date predominantly attention as a contributor to inflammation-driven diseases. In our study, we investigated the cell death pathways associated with DR3. We show that in addition to apoptosis, DR3 can robustly trigger necroptotic cell death and provide evidence for TL1A-induced, DR3-mediated necrosome assembly...
September 3, 2016: Cellular and Molecular Life Sciences: CMLS
S B Berger, J Bertin, P J Gough
No abstract text is available yet for this article.
2016: Cell Death Discovery
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