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https://www.readbyqxmd.com/read/29789521/triad3a-induces-the-degradation-of-early-necrosome-to-limit-ripk1-dependent-cytokine-production-and-necroptosis
#1
Norah A Alturki, Scott McComb, Ardeshir Ariana, Dikchha Rijal, Robert G Korneluk, Shao-Cong Sun, Emad Alnemri, Subash Sad
Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins...
May 22, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29786671/mechanisms-of-action-and-cell-death-associated-with-clostridium-perfringens-toxins
#2
REVIEW
Mauricio A Navarro, Bruce A McClane, Francisco A Uzal
Clostridium perfringens uses its large arsenal of protein toxins to produce histotoxic, neurologic and intestinal infections in humans and animals. The major toxins involved in diseases are alpha (CPA), beta (CPB), epsilon (ETX), iota (ITX), enterotoxin (CPE), and necrotic B-like (NetB) toxins. CPA is the main virulence factor involved in gas gangrene in humans, whereas its role in animal diseases is limited and controversial. CPB is responsible for necrotizing enteritis and enterotoxemia, mostly in neonatal individuals of many animal species, including humans...
May 22, 2018: Toxins
https://www.readbyqxmd.com/read/29786074/constitutive-interferon-signaling-maintains-critical-threshold-of-mlkl-expression-to-license-necroptosis
#3
Joseph Sarhan, Beiyun C Liu, Hayley I Muendlein, Chi G Weindel, Irina Smirnova, Amy Y Tang, Vladimir Ilyukha, Maxim Sorokin, Anton Buzdin, Katherine A Fitzgerald, Alexander Poltorak
Interferons (IFNs) are critical determinants in immune-competence and autoimmunity, and are endogenously regulated by a low-level constitutive feedback loop. However, little is known about the functions and origins of constitutive IFN. Recently, lipopolysaccharide (LPS)-induced IFN was implicated as a driver of necroptosis, a necrotic form of cell death downstream of receptor-interacting protein (RIP) kinase activation and executed by mixed lineage kinase like-domain (MLKL) protein. We found that the pre-established IFN status of the cell, instead of LPS-induced IFN, is critical for the early initiation of necroptosis in macrophages...
May 21, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29783720/p53-autophagy-metastasis-link
#4
REVIEW
Tatiana V Denisenko, Anastasia D Pivnyuk, Boris Zhivotovsky
The tumor suppressor p53 as the "guardian of the genome" plays an essential role in numerous signaling pathways that control the cell cycle, cell death and in maintaining the integrity of the human genome. p53, depending on the intracellular localization, contributes to the regulation of various cell death pathways, including apoptosis, autophagy and necroptosis. Accumulated evidence suggests that this function of p53 is closely involved in the process of cancer development. Here, present knowledge concerning a p53-autophagy-metastasis link, as well as therapeutic approaches that influence this link, are discussed...
May 18, 2018: Cancers
https://www.readbyqxmd.com/read/29775594/embryogenesis-and-adult-life-in-the-absence-of-intrinsic-apoptosis-effectors-bax-bak-and-bok
#5
Francine F S Ke, Hannah K Vanyai, Angus D Cowan, Alex R D Delbridge, Lachlan Whitehead, Stephanie Grabow, Peter E Czabotar, Anne K Voss, Andreas Strasser
Intrinsic apoptosis, reliant on BAX and BAK, has been postulated to be fundamental for morphogenesis, but its precise contribution to this process has not been fully explored in mammals. Our structural analysis of BOK suggests close resemblance to BAX and BAK structures. Notably, Bok-/- Bax-/- Bak-/- animals exhibited more severe defects and died earlier than Bax-/- Bak-/- mice, implying that BOK has overlapping roles with BAX and BAK during developmental cell death. By analyzing Bok-/- Bax-/- Bak-/- triple-knockout mice whose cells are incapable of undergoing intrinsic apoptosis, we identified tissues that formed well without this process...
May 17, 2018: Cell
https://www.readbyqxmd.com/read/29775589/better-together-a-hybrid-amyloid-signals-necroptosis
#6
Dan Li, Cong Liu
A new solid-state NMR study determines the high-resolution hetero-amyloid structure of the RIPK1-RIPK3 signaling complex that is involved in mediating necroptosis. The structure demonstrates specific formation of hetero-amyloids over homo-amyloids and the structural basis for a functional amyloid to act as a platform to recruit and activate downstream partners in intracellular signaling.
May 17, 2018: Cell
https://www.readbyqxmd.com/read/29770852/notch-inhibition-counteracts-paneth-cell-death-in-absence-of-caspase-8
#7
M K Jeon, E Kaemmerer, U Schneider, M Schiffer, C Klaus, J Hennings, T Clahsen, T Ackerstaff, M Niggemann, A Schippers, T Longerich, G Sellge, C Trautwein, N Wagner, C Liedtke, N Gassler
Opposing activities of Notch and Wnt signaling regulate mucosal barrier homeostasis and differentiation of intestinal epithelial cells. Specifically, Wnt activity is essential for differentiation of secretory cells including Wnt3-producing Paneth cells, whereas Notch signaling strongly promotes generation of absorptive cells. Loss of caspase-8 in intestinal epithelium (casp8∆int ) is associated with fulminant epithelial necroptosis, severe Paneth cell death, secondary intestinal inflammation, and an increase in Notch activity...
May 16, 2018: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/29770487/inhibitory-effect-of-melatonin-on-necroptosis-via-repressing-the-ripk3-pgam5-cypd-mptp-pathway-attenuates-cardiac-microvascular-ischemia-reperfusion-injury
#8
Hao Zhou, Dandan Li, Pingjun Zhu, Qiang Ma, Toan Sam, Jin Wang, Shunying Hu, Yundai Chen, Yingmei Zhang
The molecular features of necroptosis in cardiac ischemia reperfusion (IR) injury have been extensively explored. However, there have been no studies investigating the physiological regulatory mechanisms of melatonin acting on necroptosis in cardiac IR injury. This study was designed to determine the role of necroptosis in microvascular IR injury, and investigate the contribution of melatonin in repressing necroptosis and preventing IR-mediated endothelial system collapse. Our results demonstrated that Ripk3 was primarily activated by IR injury and consequently aggravated endothelial necroptosis, microvessel barrier dysfunction, capillary hyperpermeability, the inflammation response, microcirculatory vasospasms and microvascular perfusion defects...
May 16, 2018: Journal of Pineal Research
https://www.readbyqxmd.com/read/29770331/-bauhinia-variegata-candida-fraction-induces-tumor-cell-death-by-activation-of-caspase-3-rip-and-tnf-r1-and-inhibits-cell-migration-and-invasion-in-vitro
#9
K M Santos, I N F Gomes, R J Silva-Oliveira, F E Pinto, B G Oliveira, R C R Chagas, W Romão, R M V Reis, R I M A Ribeiro
Metastasis remains the most common cause of death in cancer patients. Inhibition of metalloproteinases (MMPs) is an interesting approach to cancer therapy because of their role in the degradation of extracellular matrix (ECM), cell-cell, and cell-ECM interactions, modulating key events in cell migration and invasion. Herein, we show the cytotoxic and antimetastatic effects of the third fraction (FR3) from Bauhinia variegata candida (Bvc) stem on human cervical tumor cells (HeLa) and human peripheral blood mononuclear cells (PBMCs)...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29770189/hydrogen-inhalation-improves-mouse-neurological-outcomes-after-cerebral-ischemia-reperfusion-independent-of-anti-necroptosis
#10
Jun-Long Huang, Wen-Wu Liu, Xue-Jun Sun
This study aimed to investigate the role of necroptosis in the neuroprotection of hydrogen in a mouse model of cerebral ischemia/reperfusion (I/R) injury. C57BL mice were randomly divided into sham group, I/R group, hydrogen/oxygen group (HO), nitrogen/oxygen group (NO). Middle cerebral artery occlusion (MCAO) for 1 hour followed by reperfusion was introduced to animals which were allowed to inhale 66.7% hydrogen/33.3% oxygen for 90 minutes since the beginning of reperfusion. Mice in NO group inhaled 66.7% nitrogen/33...
January 2018: Medical Gas Research
https://www.readbyqxmd.com/read/29769287/the-protective-role-of-macrophage-migration-inhibitory-factor-in-acute-kidney-injury-after-cardiac-surgery
#11
Christian Stoppe, Luisa Averdunk, Andreas Goetzenich, Josefin Soppert, Arnaud Marlier, Sandra Kraemer, Jil Vieten, Mark Coburn, Ana Kowark, Bong-Song Kim, Gernot Marx, Steffen Rex, Akinobu Ochi, Lin Leng, Gilbert Moeckel, Andreas Linkermann, Omar El Bounkari, Alexander Zarbock, Jürgen Bernhagen, Sonja Djudjaj, Richard Bucala, Peter Boor
Acute kidney injury (AKI) represents the most frequent complication after cardiac surgery. Macrophage migration inhibitory factor (MIF) is a stress-regulating cytokine that was shown to protect the heart from myocardial ischemia-reperfusion injury, but its role in the pathogenesis of AKI remains unknown. In an observational study, serum and urinary MIF was quantified in 60 patients scheduled for elective conventional cardiac surgery with the use of cardiopulmonary bypass. Cardiac surgery triggered an increase in MIF serum concentrations, and patients with high circulating MIF (>median) 12 hours after surgery had a significantly reduced risk of developing AKI (relative risk reduction, 72...
May 16, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29766811/p2x7-receptor-associated-programmed-cell-death-in-the-pathophysiology-of-hemorrhagic-stroke
#12
Hengli Zhao, Yujie Chen, Hua Feng
Hemorrhagic stroke is a life-threatening disease characterized by a sudden rupture of cerebral blood vessels, and cell death is widely believed to occur after exposure to blood metabolites or subsequently damaged cells. Recently, programmed cell death, such as apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis, has been demonstrated to play crucial roles in the pathophysiology of stroke. However, the detailed mechanisms of these novel kinds of cell death are still unclear. The P2X7 receptor, previously known for its cytotoxic activity, is an ATP-gated, non-selective cation channel that belongs to the family of ionotropic P2X receptors...
May 15, 2018: Current Neuropharmacology
https://www.readbyqxmd.com/read/29763682/melatonin-attenuates-arsenic-induced-nephropathy-via-the-regulation-of-oxidative-stress-and-inflammatory-signaling-cascades-in-mice
#13
Sayanta Dutta, Sukanya Saha, Sushweta Mahalanobish, Pritam Sadhukhan, Parames C Sil
Arsenic is a potent inducer of several acute and chronic nephrotoxic disorders. It promotes deleterious phenomenon like oxidative stress, inflammation, cell death and altered glucose uptake leading to distorted kidney homeostasis that end up in chronic kidney disease. This study investigated the possible protective role of melatonin; a natural antioxidant produced by the pineal gland, against arsenic induced nephrotoxicity. Melatonin successfully ameliorated arsenic induced renal toxicity both in in vitro and in vivo models...
May 12, 2018: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29760953/hyperglycemia-potentiates-a-shift-from-apoptosis-to-rip1-dependent-necroptosis
#14
William D McCaig, Payal S Patel, Sergey A Sosunov, Nicole L Shakerley, Tori A Smiraglia, Miranda M Craft, Katharine M Walker, Matthew A Deragon, Vadim S Ten, Timothy J LaRocca
Apoptosis and necroptosis are the primary modes of eukaryotic cell death, with apoptosis being non-inflammatory while necroptosis is highly inflammatory. We previously demonstrated that, once activated, necroptosis is enhanced by hyperglycemia in several cell types. Here, we determine if hyperglycemia affects apoptosis similarly. We show that hyperglycemia does not enhance extrinsic apoptosis but potentiates a shift to RIP1-dependent necroptosis. This is due to increased levels and activity of RIP1, RIP3, and MLKL, as well as decreased levels and activity of executioner caspases under hyperglycemic conditions following stimulation of apoptosis...
2018: Cell Death Discovery
https://www.readbyqxmd.com/read/29760187/lipopolysaccharide-lps-binding-protein-stimulates-cd14-dependent-toll-like-receptor-4-internalization-and-lps-induced-tbk1-ikk%C3%AF%C2%B5-irf3-axis-activation
#15
Hiroki Tsukamoto, Shino Takeuchi, Kanae Kubota, Yohei Kobayashi, Sao Kozakai, Ippo Ukai, Ayumi Shichiku, Misaki Okubo, Muneo Numasaki, Yoshitomi Kanemitsu, Yotaro Matsumoto, Tomonori Nochi, Kouichi Watanabe, Hisashi Aso, Yoshihisa Tomioka
Toll-like receptor 4 (TLR4) is an indispensable immune receptor for lipopolysaccharide (LPS), a major component of the Gram-negative bacterial cell wall. Following LPS stimulation, TLR4 transmits the signal from the cell surface and becomes internalized in an endosome. However, the spatial regulation of TLR4 signaling is not fully understood. Here, we investigated the mechanisms of LPS-induced TLR4 internalization and clarified the roles of the extracellular LPS-binding molecules, LPS-binding protein (LBP), and glycerophosphatidylinositol-anchored protein (CD14)...
May 14, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29759140/the-involvement-of-neuroinflammation-and-necroptosis-in-the-hippocampus-during-vascular-dementia
#16
Mourad Belkhelfa, Narimene Beder, Daya Mouhoub, Manel Amri, Rafa Hayet, Nabila Tighilt, Souad Bakheti, Soraya Laimouche, Djamel Azzouz, Rachid Belhadj, Chafia Touil-Boukoffa
The prevalence of vascular dementia is increasing at an alarming rate. The Confirmation of the clinical diagnosis of vascular dementia depends on post-mortem examination of the brain. In our study, we investigated the vascular disease and neuroinflammation during vascular dementia. Our results showed a β-amyloid deposits, neovascularization, neuronal hypertrophy and neuroinflammation in the hippocampus tissue. Interestingly, the neuroinflammation was characterized by a higher expression of TNF-α, IL-1β, TGF-β and iNOS which are TLR4/RelA pathway dependent...
July 15, 2018: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/29749404/endogenous-hepcidin-synthesis-protects-the-distal-nephron-against-hemin-and-hemoglobin-mediated-necroptosis
#17
Rachel P L van Swelm, Madelon Vos, Frank Verhoeven, Frank Thévenod, Dorine W Swinkels
Hemoglobinuria is associated with kidney injury in various hemolytic pathologies. Currently, there is no treatment available and its pathophysiology is not completely understood. Here we studied the potential detrimental effects of hemoglobin (Hb) exposure to the distal nephron (DN). Involvement of the DN in Hb kidney injury was suggested by the induction of renal hepcidin synthesis (p < 0.001) in mice repeatedly injected with intravenous Hb. Moreover, the hepcidin induction was associated with a decline in urinary kidney injury markers 24p3/NGAL and KIM1, suggesting a role for hepcidin in protection against Hb kidney injury...
May 10, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29746630/ripk3-mlkl-mediated-neuronal-necroptosis-modulates-the-m1-m2-polarization-of-microglia-macrophages-in-the-ischemic-cortex
#18
Jiping Yang, Youyi Zhao, Li Zhang, Hong Fan, Chuchu Qi, Kun Zhang, Xinyu Liu, Lin Fei, Siwei Chen, Mengmeng Wang, Fang Kuang, Yazhou Wang, Shengxi Wu
Cell death and subsequent inflammation are 2 key pathological changes occurring in cerebral ischemia. Active microglia/macrophages play a double-edged role depending on the balance of their M1/M2 phenotypes. Necrosis is the predominant type of cell death following ischemia. However, how necrotic cells modulate the M1/M2 polarization of microglia/macrophages remains poorly investigated. Here, we reported that ischemia induces a rapid RIPK3/MLKL-mediated neuron-dominated necroptosis, a type of programmed necrosis...
May 9, 2018: Cerebral Cortex
https://www.readbyqxmd.com/read/29746256/glucocorticoid-receptor-dimers-control-intestinal-stat1-and-tnf-induced-inflammation-in-mice
#19
Marlies Ballegeer, Kelly Van Looveren, Steven Timmermans, Melanie Eggermont, Sofie Vandevyver, Fabien Thery, Karen Dendoncker, Jolien Souffriau, Jolien Vandewalle, Lise Van Wyngene, Riet De Rycke, Nozomi Takahashi, Peter Vandenabeele, Jan Tuckermann, Holger M Reichardt, Francis Impens, Rudi Beyaert, Karolien De Bosscher, Roosmarijn E Vandenbroucke, Claude Libert
Tumor Necrosis Factor (TNF) is an important mediator in numerous inflammatory diseases, e.g., in inflammatory bowel diseases (IBD). In IBD, acute increases in TNF production can lead to disease flares. Glucocorticoids (GCs), which are steroids that bind and activate the glucocorticoid receptor (GR), are able to protect animals and humans against acute TNF-induced inflammatory symptoms. Mice with a poor transcriptional response of GR-dimer-dependent target genes were studied in a model of TNF-induced lethal inflammation...
May 10, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29743559/antigen-specific-primed-cytotoxic-t-cells-eliminate-tumour-cells-in-vivo-and-prevent-tumour-development-regardless-of-the-presence-of-anti-apoptotic-mutations-conferring-drug-resistance
#20
Paula Jaime-Sánchez, Elena Catalán, Iratxe Uranga-Murillo, Nacho Aguiló, Llipsy Santiago, Pilar M Lanuza, Diego de Miguel, Maykel A Arias, Julián Pardo
Cytotoxic CD8+ T (Tc) cells are the main executors of transformed and cancer cells during cancer immunotherapy. The latest clinical results evidence a high efficacy of novel immunotherapy agents that modulate Tc cell activity against bad prognosis cancers. However, it has not been determined yet whether the efficacy of these treatments can be affected by selection of tumoural cells with mutations in the cell death machinery, known to promote drug resistance and cancer recurrence. Here, using a model of prophylactic tumour vaccination based on the LCMV-gp33 antigen and the mouse EL4 T lymphoma, we analysed the molecular mechanism employed by Tc cells to eliminate cancer cells in vivo and the impact of mutations in the apoptotic machinery on tumour development...
May 9, 2018: Cell Death and Differentiation
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