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Jinyu Pan, Lu Lu, Xuyang Wang, Dian Liu, Jingjing Tian, Hui Liu, Mingjun Zhang, Fengqin Xu, Fengshuang An
BACKGROUND: Atherosclerosis (AS) is a common pathological basis of various cardiovascular and cerebrovascular diseases. Plaque formation is initiated and triggered by vascular smooth musclecells (VSMCs) migration in vascular wall, which gradually aggravates atherosclerosis progression. Absent in melanoma 2 (AIM2), a member of HIN-200 family, plays an important role in activating inflammasome. However, the role of AIM2 in atherosclerotic plaque progression outside of the inflammasome has not yet been reported...
February 12, 2018: Biochemical and Biophysical Research Communications
Yuhei Maruzuru, Takeshi Ichinohe, Ryota Sato, Kensuke Miyake, Tokuju Okano, Toshihiko Suzuki, Takumi Koshiba, Naoto Koyanagi, Shumpei Tsuda, Mizuki Watanabe, Jun Arii, Akihisa Kato, Yasushi Kawaguchi
The AIM2 inflammasome is activated by DNA, leading to caspase-1 activation and release of pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-18, which are critical mediators in host innate immune responses against various pathogens. Some viruses employ strategies to counteract inflammasome-mediated induction of pro-inflammatory cytokines, but their in vivo relevance is less well understood. Here we show that the herpes simplex virus 1 (HSV-1) tegument protein VP22 inhibits AIM2-dependent inflammasome activation...
February 14, 2018: Cell Host & Microbe
Hailin Zhao, Han Huang, Azeem Alam, Qian Chen, Ka Chuen Suen, Jiang Cui, Qizhe Sun, Rele Ologunde, Wenwen Zhang, Qingquan Lian, Daqing Ma
Clinical evidence indicated a possible link between renal injury and remote liver injury. Herein, we investigated whether extracellular histone mediates remote hepatic damage following renal graft ischemia-reperfusion injury, whilst vascular endothelial growth factor (VEGF) is protective against remote hepatic injury. In vitro, hepatocyte HepG2 cultures were treated with histone. In vivo, the Brown-Norway renal graft was stored in 4°C preserving solution for 24 hours and then transplanted into Lewis rat recipient; blood samples and livers from recipients were harvested 24 hours after surgery...
February 15, 2018: American Journal of Transplantation
Mariusz Matyszewski, Seamus R Morrone, Jungsan Sohn
The AIM2-ASC inflammasome is a filamentous signaling platform essential for mounting host defense against cytoplasmic dsDNA arising not only from invading pathogens but also from damaged organelles. Currently, the design principles of its underlying signaling network remain poorly understood at the molecular level. We show here that longer dsDNA is more effective in inducing AIM2 assembly, its self-propagation, and downstream ASC polymerization. This observation is related to the increased probability of forming the base of AIM2 filaments, and indicates that the assembly discerns small dsDNA as noise at each signaling step...
February 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Takanori Komada, Hyunjae Chung, Arthur Lau, Jaye M Platnich, Paul L Beck, Hallgrimur Benediktsson, Henry J Duff, Craig N Jenne, Daniel A Muruve
Nonmicrobial inflammation contributes to CKD progression and fibrosis. Absent in melanoma 2 (AIM2) is an inflammasome-forming receptor for double-stranded DNA. AIM2 is expressed in the kidney and activated mainly by macrophages. We investigated the potential pathogenic role of the AIM2 inflammasome in kidney disease. In kidneys from patients with diabetic or nondiabetic CKD, immunofluorescence showed AIM2 expression in glomeruli, tubules, and infiltrating leukocytes. In a mouse model of unilateral ureteral obstruction (UUO), Aim2 deficiency attenuated the renal injury, fibrosis, and inflammation observed in wild-type (WT) littermates...
February 9, 2018: Journal of the American Society of Nephrology: JASN
Chia-Ming Chang, Mong-Lien Wang, Kai-Hsi Lu, Yi-Ping Yang, Chi-Mou Juang, Peng-Hui Wang, Ren-Jun Hsu, Mu-Hsien Yu, Cheng-Chang Chang
The coexistence of endometriosis (ES) with ovarian clear cell carcinoma (CCC) or endometrioid carcinoma (EC) suggested that malignant transformation of ES leads to endometriosis associated ovarian carcinoma (EAOC). However, there is still lack of an integrating data analysis of the accumulated experimental data to provide the evidence supporting the hypothesis of EAOC transformation. Herein we used a function-based analytic model with the publicly available microarray datasets to investigate the expression profiling between ES, CCC, and EC...
January 9, 2018: Oncotarget
Sebastian Virreira Winter, Arturo Zychlinsky
Inflammasomes are cytosolic complexes that mature and secrete the inflammatory cytokines IL-1β and IL-18 and induce pyroptosis. The NLRP3 inflammasome detects many pathogen- and danger-associated molecular patterns, and reactive oxygen/nitrogen species (ROS/RNS) have been implicated in its activation. The phenazine pyocyanin (PCN) is a virulence factor of Pseudomonas aeruginosa and generates superoxide in cells. Here, we report that PCN inhibits IL-1β and IL-18 release and pyroptosis upon NLRP3 inflammasome activation in macrophages by preventing speck formation and Caspase-1 maturation...
February 6, 2018: Journal of Biological Chemistry
Carlo Marchetti, Benjamin Swartzwelter, Fabia Gamboni, Charles P Neff, Katrin Richter, Tania Azam, Sonia Carta, Isak Tengesdal, Travis Nemkov, Angelo D'Alessandro, Curtis Henry, Gerald S Jones, Scott A Goodrich, Joseph P St Laurent, Terry M Jones, Curtis L Scribner, Robert B Barrow, Roy D Altman, Damaris B Skouras, Marco Gattorno, Veronika Grau, Sabina Janciauskiene, Anna Rubartelli, Leo A B Joosten, Charles A Dinarello
Activation of the NLRP3 inflammasome induces maturation of IL-1β and IL-18, both validated targets for treating acute and chronic inflammatory diseases. Here, we demonstrate that OLT1177, an orally active β-sulfonyl nitrile molecule, inhibits activation of the NLRP3 inflammasome. In vitro, nanomolar concentrations of OLT1177 reduced IL-1β and IL-18 release following canonical and noncanonical NLRP3 inflammasome activation. The molecule showed no effect on the NLRC4 and AIM2 inflammasomes, suggesting specificity for NLRP3...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
Nikolaus Deigendesch, Arturo Zychlinsky, Felix Meissner
Inflammasomes are multimeric protein complexes that are activated through a NOD-like receptor and regulate the proteolytic activation of caspase-1 and cytokines, like IL-1β. The NLRP3 inflammasome is implicated in many human pathologies including infections, autoinflammatory syndromes, chronic inflammation, and metabolic diseases; however, the molecular mechanisms of activation are not fully understood. In this study we show that NLRP3 inflammasome activation requires intracellular copper. A clinically approved copper chelator, tetrathiomolybdate, inhibited the canonical NLRP3 but not the AIM2, NLRC4, and NLRP1 inflammasomes or NF-κB-dependent priming...
January 22, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
David E Place, Parimal Samir, Rajendra Karki, Benoit Briard, Peter Vogel, Thirumala-Devi Kanneganti
Activation of the multimeric inflammasome complex leads to inflammatory responses to biotic and abiotic triggers. The inflammasome sensor, Nod-like receptor family Pyrin domain containing 3 (NLRP3), is activated by a range of stimuli and is tightly regulated to restrict excessive inflammation. Because NLRP3 responds broadly to cellular insults and regulates cell death similar to the stress-activated apoptosis signal-regulating kinases 1 and 2 (ASK1/2), we hypothesized that ASK1/2 may regulate NLRP3 activity...
January 15, 2018: American Journal of Pathology
Jennifer Sand, Eric Haertel, Thomas Biedermann, Emmanuel Contassot, Ernst Reichmann, Lars E French, Sabine Werner, Hans-Dietmar Beer
Inflammasomes are multimeric protein complexes that assemble upon sensing of a variety of stress factors. Their formation results in caspase-1-mediated activation and secretion of the pro-inflammatory cytokines pro-interleukin(IL)-1β and -18, which induce an inflammatory response. Inflammation is supported by a lytic form of cell death, termed pyroptosis. Innate immune cells, such as macrophages or dendritic cells, express and activate inflammasomes. However, it has also been demonstrated that human primary keratinocytes activate different types of inflammasomes in vitro, for example, upon UVB irradiation or viral infection...
January 18, 2018: Cell Death & Disease
Dave Boucher, Amy Chan, Connie Ross, Kate Schroder
The caspase-1 protease is a core component of multiprotein inflammasome complexes, which play a critical role in regulating the secretion of mature, bioactive pro-inflammatory cytokines interleukin (IL)-1β and IL-18. The activity of caspase-1 is often measured indirectly, by monitoring cleavage of cellular caspase-1 substrates, processing of caspase-1 itself, or by quantifying cell death. Here we describe methods for eliciting caspase-1 activity in murine macrophages, via activation of the NLRP3, NAIP/NLRC4 or AIM2 inflammasomes...
2018: Methods in Molecular Biology
Yanqiong Ye, Xiaoli Wang, Qian Cai, Jian Zhuang, Xiaohua Tan, Wei He, Mingyi Zhao
To explore the effect of taxifolin on H2O2-induced pyroptosis in H9C2 cells and the possible mechanisms.
 Methods: The H9C2 cells was divided into 3 groups: a control group, a hydrogen peroxide (H2O2)group and a taxifolin group. The morphology of H9C2 cells was observed by inverted phase contrast microscope. The mitochondrial membrane potential was measured by JC-1 staining and flow cytometry. The alteration of the level of reactive oxygen species (ROS) was detected by specific mitochondrial probe. The protein levels of cysteinyl aspartate specific proteinase-1 (caspase-1)was determined by Western blot...
December 28, 2017: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
Jérôme Lugrin, Fabio Martinon
Recognition of pathogens and altered self must be efficient and highly specific to orchestrate appropriate responses while limiting excessive inflammation and autoimmune reaction to normal self. AIM2 is a member of innate immune sensors that detects the presence of DNA, arguably the most conserved molecules in living organisms. However, AIM2 achieves specificity by detecting altered or mislocalized DNA molecules. It can detect damaged DNA, and the aberrant presence of DNA within the cytosolic compartment such as genomic DNA released into the cytosol upon loss of nuclear envelope integrity...
January 2018: Immunological Reviews
Catarina Addobbati, Heidi Lacerda Alves da Cruz, José Eduardo Adelino, Amanda Luíze Melo Tavares Ramos, Thiago Sotero Fragoso, Alexandre Domingues, Ângela Luiza Branco Pinto Duarte, Renê Donizeti Ribeiro Oliveira, Paulo Louzada-Júnior, Eduardo Antônio Donadi, Alessandra Pontillo, Jaqueline de Azevêdo Silva, Sergio Crovella, Paula Sandrin-Garcia
OBJECTIVE: In the present study, we analyzed the possible association of inflammasome gene variants and expression to rheumatoid arthritis (RA)'s development and severity in the Brazilian population. MATERIALS AND METHODS: Thirteen single nucleotide polymorphisms within six inflammasome genes (NLRP1, NLRP3, NLRC4, AIM2, CARD8, CASP1) as well as IL1B and IL18 genes in two different Brazilian populations (from Northeast and Southeast Brazil) were analyzed. We also evaluated inflammasome gene expression profile in resting and LPS + ATP-treated monocytes from RA patients and healthy individuals...
December 11, 2017: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
Weiming Mo, Jun Liu, Zengyu Zhang, Hong Yu, Aiping Yang, Fei Qu, Pingfang Hu, Zhuo Liu, Fengpei Hu
PURPOSE: Autism spectrum disorder (ASD) is a group of developmental brain disorders caused by genetic and environmental factors. The objective of this study was to investigate whether single nucleotide polymorphisms (SNPs) in genes related to immune function were associated with ASD in Chinese Han children. MATERIALS AND METHODS: A total of 201 children with ASD and 200 age- and gender-matched healthy controls were recruited from September 2012 to June 2106. A TaqMan probe-based approach was used to genotype SNPs corresponding to rs28532698 and rs4301112 in CD157, rs855867 in AIM2, and rs2237126 in JARID2...
December 7, 2017: Nordic Journal of Psychiatry
Miriam M Costa Franco, Fernanda Marim, Erika S Guimarães, Natan R G Assis, Daiane M Cerqueira, Juliana Alves-Silva, Jerome Harms, Gary Splitter, Judith Smith, Thirumala-Devi Kanneganti, Nina M G P de Queiroz, Delia Gutman, Glen N Barber, Sergio C Oliveira
Immunity against microbes depends on recognition of pathogen-associated molecular patterns by innate receptors. Signaling pathways triggered by Brucella abortus DNA involves TLR9, AIM2, and stimulator of IFN genes (STING). In this study, we observed by microarray analysis that several type I IFN-associated genes, such as IFN-β and guanylate-binding proteins (GBPs), are downregulated in STING knockout (KO) macrophages infected with Brucella or transfected with DNA. Additionally, we determined that STING and cyclic GMP-AMP synthase (cGAS) are important to engage the type I IFN pathway, but only STING is required to induce IL-1β secretion, caspase-1 activation, and GBP2 and GBP3 expression...
December 4, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Dong-Won Seo, Yong-Il Cho, Suna Gu, Da-Hee Kim, Young-Joo Yi, Sang-Myeong Lee
The inflammasome is a multiprotein signaling complex that mediates inflammatory innate immune responses through caspase 1 activation and subsequent IL-1β secretion. Nonetheless, its aberrant activation often leads to inflammatory diseases. Therefore, targeting the inflammasome holds promise for the treatment of inflammation-related diseases. Our study showed that a hot-water extract of Sanguisorba officinalis (HSO) effectively suppressed inflammasome activation triggered by ATP, nigericin, microbial pathogens, and dsDNA in bone marrow-derived macrophages (BMDMs)...
November 29, 2017: Microbiology and Immunology
Shiho Suzuki, Toshihiko Suzuki, Hitomi Mimuro, Tsunehiro Mizushima, Chihiro Sasakawa
Shigella deploys a unique mechanism to manipulate macrophage pyroptosis by delivering the IpaH7.8 E3 ubiquitin ligase via its type III secretion system. IpaH7.8 ubiquitinates glomulin (GLMN) and elicits its degradation, thereby inducing inflammasome activation and pyroptotic cell death of macrophages. Here, we show that GLMN specifically binds cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1 and cIAP2), members of the inhibitor of apoptosis (IAP) family of RING-E3 ligases, which results in reduced E3 ligase activity, and consequently inflammasome-mediated death of macrophages...
November 30, 2017: EMBO Reports
Lev Grinstein, Hella Luksch, Felix Schulze, Avril A B Robertson, Matthew A Cooper, Angela Rösen-Wolff, Stefan Winkler
The proinflammatory protease caspase-1 plays pivotal roles in central pathways of innate immunity, thereby contributing to pathogen clearance. Beside its physiological role, dysregulated activity of caspase-1 is known to contribute to an increasing number of diseases. In this study we optimized and validated a low-volume human whole blood assay facilitating the measurement of caspase-1 activation and inflammasome-related gene expression upon stimulation of the NLRP3, NLRC4 or AIM2 inflammasome. Using the NLRP3 inflammasome specific inhibitor MCC950 we were able to measure the activity of canonical or alternative NLRP3 pathways, AIM2 and NLRC4 inflammasomes in whole blood...
November 25, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
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