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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
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
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
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
Hua Zhou, Erin Harberts, Rita Fishelevich, Anthony A Gaspari
UVR-induced apoptosis in cutaneous antigen presenting cells (APC) causes systemic immune suppression and is dependent on TLR4/MyD88 signaling, but the apoptotic signaling pathways have not been defined. Macrophages pre-treated with lipopolysaccharide (LPS) were unresponsive to subsequent LPS treatment; however, but were susceptible to UVR-induced apoptosis. Macrophage survival and apoptotic events after UVR were also unaffected by treatment with TLR4 antagonists, a blocking IgG or a TLR4 analog antagonist, suggesting that UVR cell death is independent of a soluble ligand...
September 27, 2016: Experimental Dermatology
D G McDonald, D Jacqmin, W A Vandergrift, S Lindhorst, D Cachia, V K Abhay, K N Vanek, N L Banik, J M Jenrette, P Giglio, S J Patel, A Das
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
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
Johanna Louhimo, Michael L Steer, George Perides
BACKGROUND AND AIMS: Severe acute pancreatitis is characterized by acinar cell death and inflammation. Necroptosis is an aggressive and pro-inflammatory mode of cell death that can be prevented by necrostatin-1 administration or RIP3 deletion. METHODS: Mouse pancreatic acinar cells were incubated with supramaximally stimulating concentrations of caerulein or sub-micellar concentrations of TLCS and necroptosis was inhibited by either addition of necrostatin or by RIP3 deletion...
July 2016: Cellular and Molecular Gastroenterology and Hepatology
Tatsuya Yamada, Yoshihiro Adachi, Masahiro Fukaya, Miho Iijima, Hiromi Sesaki
Mitochondria are dynamic organelles that divide and fuse to modulate their number and shape. We have previously reported that the loss of dynamin-related protein 1 (Drp1), which mediates mitochondrial division, leads to the degeneration of cerebellar Purkinje cells in mice. Because Drp1 has been shown to be important for apoptosis and necroptosis, it is puzzling how Purkinje neurons die in the absence of Drp1. In this study, we tested whether neurodegeneration involves necrotic cell death by generating Purkinje cell-specific Drp1-knockout (KO) mice that lack the receptor-interacting protein kinase 3 (Rip3), which regulates necroptosis...
September 15, 2016: American Journal of Pathology
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
Jian-Ming Zhou, Sha-Sha Gu, Wang Hong Mei, Jun Zhou, Zhen Zhong Wang, Wei Xiao
Ginkgolide and bilobalide are major trilactone constituent of Ginkgo biloba leaves and have been shown to exert powerful neuroprotective properties. The aims of this study were to observe the inhibitory effects of ginkgolide and bilobalide on the activation of microglial cells induced by oxygen-glucose deprivation and reoxygenation (OGD/R) and the specific mechanisms by which these effects are mediated. For detecting whether ginkgolide and bilobalide increased cell viability in a dose-dependent manner, BV2 cells were subjected to oxygen-glucose deprivation for 4 h followed by 3 h reoxygenation with various concentrations of drugs (6...
August 25, 2016: Cell Stress & Chaperones
S B Berger, J Bertin, P J Gough
No abstract text is available yet for this article.
2016: Cell Death Discovery
Denuja Karunakaran, Michele Geoffrion, Lihui Wei, Wei Gan, Laura Richards, Prakriti Shangari, Ella M DeKemp, Rachelle A Beanlands, Ljubica Perisic, Lars Maegdefessel, Ulf Hedin, Subash Sad, Liang Guo, Frank D Kolodgie, Renu Virmani, Terrence Ruddy, Katey J Rayner
Atherosclerosis results from maladaptive inflammation driven primarily by macrophages, whose recruitment and proliferation drive plaque progression. In advanced plaques, macrophage death contributes centrally to the formation of plaque necrosis, which underlies the instability that promotes plaque rupture and myocardial infarction. Hence, targeting macrophage cell death pathways may offer promise for the stabilization of vulnerable plaques. Necroptosis is a recently discovered pathway of programmed cell necrosis regulated by RIP3 and MLKL kinases that, in contrast to apoptosis, induces a proinflammatory state...
July 2016: Science Advances
Jeong-Min Hong, Seok-Joo Kim, Sun-Mee Lee
Ischemia and reperfusion (I/R) is a complex phenomenon involving massive inflammation and cell death. Necroptosis refers to a newly described cell death as "programmed necrosis" that is controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, which is involved in the pathogenesis of several inflammatory diseases. Autophagy is an essential cytoprotective system that is rapidly activated in response to various stimuli and involves crosstalk between different modes of cell death and inflammation. In this study, we investigated pattern changes in necroptosis and its role in autophagy signaling during hepatic I/R...
October 1, 2016: Toxicology and Applied Pharmacology
M Cristina de Almagro, Tatiana Goncharov, Anita Izrael-Tomasevic, Stefanie Duttler, Matthias Kist, Eugene Varfolomeev, Xiumin Wu, Wyne P Lee, Jeremy Murray, Joshua D Webster, Kebing Yu, Donald S Kirkpatrick, Kim Newton, Domagoj Vucic
Proper regulation of cell death signaling is crucial for the maintenance of homeostasis and prevention of disease. A caspase-independent regulated form of cell death called necroptosis is rapidly emerging as an important mediator of a number of human pathologies including inflammatory bowel disease and ischemia-reperfusion organ injury. Activation of necroptotic signaling through TNF signaling or organ injury leads to the activation of kinases receptor-interacting protein kinases 1 and 3 (RIP1 and RIP3) and culminates in inflammatory cell death...
August 12, 2016: Cell Death and Differentiation
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