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Su Hwan Lee, Ju Hye Shin, Joo Han Song, Ah Young Leem, Moo Suk Park, Young Sam Kim, Joon Chang, Kyung Soo Chung
Insulin-like growth factor-1 (IGF-1) levels are known to increase in the bronchoalveolar lavage fluid (BALF) of patients with acute respiratory distress syndrome. Herein, we investigated the role of IGF-1 in lipopolysaccharide (LPS)-induced lung injury. In LPS-treated cells, expressions of receptor-interacting protein 3 (RIP3) and phosphorylated mixed lineage kinase domain-like protein (MLKL) were decreased in IGF-1 receptor small interfering RNA (siRNA)-treated cells compared to control cells. The levels of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-10, tumour necrosis factor-α, and macrophage inflammatory protein 2/C-X-C motif chemokine ligand 2 in the supernatant were significantly reduced in IGF-1 receptor siRNA-treated cells compared to control cells...
March 12, 2018: Biochemical and Biophysical Research Communications
Michal Lusthaus, Niv Mazkereth, Natalie Donin, Zvi Fishelson
The complement system participates in the pathogenesis of many diseases. Complement activation produces several active protein complexes and peptides, including the terminal C5b-9 complexes. It was reported that C5b-9 complexes insert into the plasma membrane and cause membrane perturbation, intracellular calcium surge, metabolic depletion, and osmotic lysis. Previously, we showed that complement-dependent cytotoxicity (CDC) is regulated by JNK and Bid. Here, we demonstrate that three mediators in TNFα-induced necroptosis (regulated necrosis), the receptor-interacting protein kinases, receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like protein (MLKL), are activated by complement and contribute to CDC...
2018: Frontiers in Immunology
Felix Lauffer, Manja Jargosch, Linda Krause, Natalie Garzorz-Stark, Regina Franz, Sophie Roenneberg, Alexander Böhner, Nikola S Mueller, Fabian J Theis, Carsten B Schmidt-Weber, Tilo Biedermann, Stefanie Eyerich, Kilian Eyerich
Interface dermatitis (ID) is a characteristic histological pattern which occurs in autoimmune and chronic inflammatory skin diseases. It is unknown whether a common mechanism orchestrates this distinct type of skin inflammation. Here we investigated the overlap of two different ID positive skin diseases, lichen planus (LP) and lupus erythematosus (LE). The shared transcriptome signature pointed towards a strong type I immune response and biopsy derived T cells were dominated by IFN-γ and TNF-α positive cells...
March 8, 2018: Journal of Investigative Dermatology
Samuel C Cerps, Mandy Menzel, Irma Mahmutovic Persson, Leif Bjermer, Hamid Akbarshahi, Lena Uller
Defective production of antiviral interferon (IFN)-β is thought to contribute to rhinovirus-induced asthma exacerbations. These exacerbations are associated with elevated lung levels of lactate dehydrogenase (LDH), indicating occurrence of cell necrosis. We thus hypothesized that reduced lung IFN-β could contribute to necrotic cell death in a model of asthma exacerbations. Wild-type and IFN-β-/- mice were given saline or house dust mite (HDM) intranasally for 3 weeks to induce inflammation. Double-stranded RNA (dsRNA) was then given for additional 3 days to induce exacerbation...
March 9, 2018: Scientific Reports
Manuela Hefele, Iris Stolzer, Barbara Ruder, Gui-Wei He, Mousumi Mahapatro, Stefan Wirtz, Markus F Neurath, Claudia Günther
Although induction of host cell death is a pivotal step during bacteria-induced gastroenteritis, the molecular regulation remains to be fully characterized. To expand our knowledge, we investigated the role of the central cell death regulator Caspase-8 in response to Salmonella Typhimurium. Here, we uncovered that intestinal salmonellosis was associated with strong upregulation of members of the host cell death machinery in intestinal epithelial cells (IECs) as an early event, suggesting that elimination of infected IECs represents a host defense strategy...
March 8, 2018: Mucosal Immunology
Ying Zhou, Chao Niu, Bo Ma, Xiaoyan Xue, Zhi Li, Zhou Chen, Fen Li, Shan Zhou, Xiaoxing Luo, Zheng Hou
Given its high resistance, enhanced virulence, and high transmissibility, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) pneumonia is highly associated with high morbidity and mortality. Anti-virulence therapy is a promising strategy that bypasses the evolutionary pressure on the bacterium to develop resistance. RNAIII-inhibiting peptide (RIP), as an accessory gene regulator (agr)-specific inhibitor, significantly restricts the virulence of S. aureus and protects infected mice from death by blocking the agr quorum sensing system...
March 2, 2018: Cell Death & Disease
Anne von Mässenhausen, Wulf Tonnus, Nina Himmerkus, Simon Parmentier, Danish Saleh, Diego Rodriquez, Jiraporn Ousingsawat, Rosalind L Ang, Joel M Weinberg, Ana B Sanz, Alberto Ortiz, Adrian Zierleyn, Jan Ulrich Becker, Blandine Baratte, Nathalie Desban, Stéphane Bach, Ina Maria Schiessl, Shoko Nogusa, Siddharth Balachandran, Hans Joachim Anders, Adrian T Ting, Markus Bleich, Alexei Degterev, Karl Kunzelmann, Stefan R Bornstein, Douglas R Green, Christian Hugo, Andreas Linkermann
Receptor-interacting protein kinases 1 and 3 (RIPK1/3) have best been described for their role in mediating a regulated form of necrosis, referred to as necroptosis. During this process, RIPK3 phosphorylates mixed lineage kinase domain-like (MLKL) to cause plasma membrane rupture. RIPK3-deficient mice have recently been demonstrated to be protected in a series of disease models, but direct evidence for activation of necroptosis in vivo is still limited. Here, we sought to further examine the activation of necroptosis in kidney ischemia-reperfusion injury (IRI) and from TNFα-induced severe inflammatory response syndrome (SIRS), two models of RIPK3-dependent injury...
March 2, 2018: Cell Death & Disease
Mohammad Ali, Edward S Mocarski
Proteasome inhibitors have achieved clinical success because they trigger intrinsic and extrinsic cell death to eliminate susceptible human cancers. The ubiquitin-proteasome protein degradation system regulates signaling pathways by controlling levels of components such as cellular inhibitor of apoptosis (cIAP)1 and cIAP2 in TNF-mediated cell death. Here, we sought to evaluate the contribution of necroptosis to the cell death pattern induced by the specific proteasome inhibitor Carfilzomib (Cf). Proteasome inhibitor-sensitive multiple myeloma cell lines die in response to Cf by apoptosis in combination with serine protease-dependent death, without any contribution of RIPK3-dependent necroptosis...
March 1, 2018: Cell Death & Disease
Yanling Guo, Xiaxia Wu, Qin Wu, Yuanfu Lu, Jingshan Shi, Xiuping Chen
Ulcerative colitis (UC) is a chronic and relapsing inflammatory disorder of the colon and rectum with increasing morbidity in recent years. 15,16-dihydrotanshinone Ӏ (DHT) is a natural product with multiple bioactivities. In this study, we aimed to investigate the protective effect and potential mechanisms of DHT on UC. Dextran sulfate sodium salt (DSS) was administrated in drinking water for 7 days to induce UC in mice. DHT (10 and 25 mg/kg) significantly alleviated DSS-induced body weight loss, disease activity index (DAI) scores, and improved histological alterations of colon tissues...
February 26, 2018: Toxicology and Applied Pharmacology
Eugene Cho, Jong-Kook Lee, Eunji Park, Chang Ho Seo, Tudor Luchian, Yoonkyung Park
The antimicrobial peptide HPA3 shows anticancer activity in gastric cancer and leukaemia. However, how HPA3 exerts its anticancer activity, as well as whether it also exhibits activity in other cancers, remains unknown. Therefore, the aim of this study was to evaluate the anticancer activity of HPA3 and its analogues in colon cancer and to elucidate the mechanisms responsible for this activity. HPA3P decreased cell viability, whereas HPA3 and HPA3P2 did not decrease cell viability in colon cancer cells compared with control cells...
January 30, 2018: Oncotarget
Yu Saito, Shota Moriya, Hiromi Kazama, Kazuhiro Hirasawa, Kana Miyahara, Hiroko Kokuba, Hirotsugu Hino, Hiroyuki Kikuchi, Naoharu Takano, Masaki Hiramoto, Kiyoaki Tsukahara, Keisuke Miyazawa
The maintenance of the intracellular level of amino acids is crucial for cellular homeostasis. This is carried out via the regulation of both the influx from the extracellular environment and the recycling of intracellular resources. Since epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, including gefitinib (GEF) have been reported to induce the apoptosis of several cancer cell lines, in the present study, we examined whether the cytotoxic effects of GEF are further enhanced under amino acid starvation (AAS) culture conditions...
February 23, 2018: International Journal of Oncology
Zai-Ming Liu, Qian-Xue Chen, Zhi-Biao Chen, Dao-Feng Tian, Ming-Chang Li, Jun-Min Wang, Long Wang, Bao-Hui Liu, Shen-Qi Zhang, Fei Li, Hui Ye, Long Zhou
Traumatic brain injury (TBI) is a leading cause of disability and mortality in young adults worldwide. The pathophysiology is not fully understood. Programmed necrosis (necroptosis) is a newly identified mechanism of cell death combining features of both apoptosis and necrosis. Receptor-interacting protein 3 (RIP3) plays an important role in programmed necrosis. However, the effect of RIP3-related pathway in TBI is little to be known. We attempted to explore the significance of RIP3 in regulating TBI in vivo...
February 19, 2018: Biochemical and Biophysical Research Communications
Simone Fulda
Necroptosis represents a form of programmed cell death that can be engaged by various upstream signals, for example by ligation of death receptors, by viral sensors or by pattern recognition receptors. It depends on several key signaling proteins, including the kinases Receptor-Interacting Protein (RIP)1 and RIP3 and the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Necroptosis has been implicated in a number of physiological and pathophysiological conditions and is disturbed in many human diseases...
February 21, 2018: Cell Cycle
Shui-Xing Yu, Wei Chen, Zhen-Zhen Liu, Feng-Hua Zhou, Shi-Qing Yan, Gui-Qiu Hu, Xiao-Xia Qin, Jie Zhang, Ke Ma, Chong-Tao Du, Jing-Min Gu, Xu-Ming Deng, Wen-Yu Han, Yong-Jun Yang
The intestinal mucosal barrier is critical for host defense against pathogens infection. Here, we demonstrate that the mixed lineage kinase-like protein (MLKL), a necroptosis effector, promotes intestinal epithelial barrier function by enhancing inflammasome activation. MLKL-/- mice were more susceptible to Salmonella infection compared with wild-type counterparts, with higher mortality rates, increased body weight loss, exacerbated intestinal inflammation, more bacterial colonization, and severe epithelial barrier disruption...
2018: Frontiers in Immunology
Marinella G Callow, Colin Watanabe, Katherine E Wickliffe, Russell Bainer, Sarah Kummerfield, Julie Weng, Trinna Cuellar, Vasantharajan Janakiraman, Honglin Chen, Ben Chih, Yuxin Liang, Benjamin Haley, Kim Newton, Michael R Costa
The necroptotic cell death pathway is a key component of human pathogen defense that can become aberrantly derepressed during tissue homeostasis to contribute to multiple types of tissue damage and disease. While formation of the necrosome kinase signaling complex containing RIPK1, RIPK3, and MLKL has been extensively characterized, additional mechanisms of its regulation and effector functions likely remain to be discovered. We screened 19,883 mouse protein-coding genes by CRISPR/Cas9-mediated gene knockout for resistance to cytokine-induced necroptosis and identified 112 regulators and mediators of necroptosis, including 59 new candidate pathway components with minimal or no effect on cell growth in the absence of necroptosis induction...
February 15, 2018: Cell Death & Disease
Katherine A Davies, Maria C Tanzer, Michael D W Griffin, Yee Foong Mok, Samuel N Young, Rui Qin, Emma J Petrie, Peter E Czabotar, John Silke, James M Murphy
The programmed cell death pathway, necroptosis, relies on the pseudokinase, Mixed Lineage Kinase domain-Like (MLKL), for cellular execution downstream of death receptor or Toll-like receptor ligation. Receptor-interacting protein kinase-3 (RIPK3)-mediated phosphorylation of MLKL's pseudokinase domain leads to MLKL switching from an inert to activated state, where exposure of the N-terminal four-helix bundle (4HB) 'executioner' domain leads to cell death. The precise molecular details of MLKL activation, including the stoichiometry of oligomer assemblies, mechanisms of membrane translocation and permeabilisation, remain a matter of debate...
February 14, 2018: Cell Death and Differentiation
Ewelina Zielinska, Agata Zauszkiewicz-Pawlak, Michal Wojcik, Iwona Inkielewicz-Stepniak
Pancreatic ductal adenocarcinoma, with the high resistance to chemotherapeutic agents, remains the fourth leading cause of cancer-death in the world. Due to the wide range of biological activity and unique properties, silver nanoparticles (AgNPs) are indicated as agents with potential to overcome barriers involved in chemotherapy failure. Therefore, in our study we decided to assess the ability of AgNPs to kill pancreatic cancer cells, and then to identify the molecular mechanism underlying this effect. Moreover, we evaluated the cytotoxicity of AgNPs against non-tumor cell of the same tissue (hTERT-HPNE cells) for comparison...
January 12, 2018: Oncotarget
Sofie Martens, Vera Goossens, Lars Devisscher, Sam Hofmans, Polien Claeys, Marnik Vuylsteke, Nozomi Takahashi, Koen Augustyns, Peter Vandenabeele
The Aurora kinase family (Aurora A, B and C) are crucial regulators of several mitotic events, including cytokinesis. Increased expression of these kinases is associated with tumorigenesis and several compounds targeting Aurora kinase are under evaluation in clinical trials (a.o. AT9283, AZD1152, Danusertib, MLN8054). Here, we demonstrate that the pan-Aurora kinase inhibitor Tozasertib (VX-680 and MK-0457) not only causes cytokinesis defects through Aurora kinase inhibition, but is also a potent inhibitor of necroptosis, a cell death process regulated and executed by the RIPK1, RIPK3 and MLKL signalling axis...
February 12, 2018: Cell Death & Disease
Hong Zhu, Aijun Sun
Programmed cell death plays an essential role in myocardial homeostasis and pathology. Three distinct forms of programmed cell death have been identified, namely apoptosis, necrosis, and autophagic cell death. Necrosis, previously known as an unregulated form of cell death, has been recognized as a highly regulated process now and attracted great attention over the past decade. Programmed necrosis mainly refers to necroptosis, pyroptosis, ferroptosis, and mitochondrial permeability transition (MPT)-dependent necrosis...
March 2018: Journal of Molecular and Cellular Cardiology
Mitsuru Imamura, Jong-Seok Moon, Kuei-Pin Chung, Kiichi Nakahira, Thangamani Muthukumar, Roman Shingarev, Stefan W Ryter, Augustine Mk Choi, Mary E Choi
Renal fibrosis is a common pathogenic response to injury in chronic kidney disease (CKD). The receptor-interacting protein kinase-3 (RIPK3), a regulator of necroptosis, has been implicated in disease pathogenesis. In mice subjected to unilateral ureteral obstruction-induced (UUO-induced) or adenine diet-induced (AD-induced) renal fibrosis, models of progressive kidney fibrosis, we demonstrate increased kidney expression of RIPK3. Mice genetically deficient in RIPK3 displayed decreased kidney fibrosis and improved kidney function relative to WT mice when challenged with UUO or AD...
February 8, 2018: JCI Insight
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