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Yuji Nadatani, Xiaofang Huo, Xi Zhang, Chunhua Yu, Edaire Cheng, Qiuyang Zhang, Kerry B Dunbar, Arianne Theiss, Thai H Pham, David H Wang, Toshio Watanabe, Yasuhiro Fujiwara, Tetsuo Arakawa, Stuart J Spechler, Rhonda F Souza
BACKGROUND & AIMS: Microbial molecular products incite intestinal inflammation by activating Toll-like receptors (TLRs) and inflammasomes of the innate immune system. This system's contribution to esophageal inflammation is not known. Gram-negative bacteria, which dominate the esophageal microbiome in reflux esophagitis, produce lipopolysaccharide (LPS), a TLR4 ligand. TLR4 signaling produces pro-interleukin (IL)1β, pro-IL18, and NOD-like receptor protein 3 (NLRP3), which prime the NLRP3 inflammasome...
July 2016: Cellular and Molecular Gastroenterology and Hepatology
Fanqi Kong, Bozhi Ye, Jiatian Cao, Xueli Cai, Lu Lin, Shanjun Huang, Weijian Huang, Zhouqing Huang
Aims: In the NOD-like receptor (NLR) family, the pyrin domain containing 3 (NLRP3) inflammasome is closely related to the progression of atherosclerosis. This study aimed to assess the effects of curcumin on NLRP3 inflammasome in phorbol 12-myristate 13-acetate (PMA)-induced macrophages and explore its underlying mechanism. Methods: Human monocytic THP-1 cells were pretreated with curcumin for 1 h and subsequently induced with PMA for 48 h. Total protein was collected for Western blot analysis. Cytokine interleukin (IL)-1β release and nuclear factor kappa B (NF-κB) p65 translocation were detected by ELISA assay and cellular NF-κB translocation kit, respectively...
2016: Frontiers in Pharmacology
Courtney R Kent, Magdalena Bryja, Helen A Gustafson, Margaret Y Kawarski, Gena Lenti, Emily N Pierce, Rachel C Knopp, Victor Ceja, Bhabna Pati, D Eric Walters, Caitlin E Karver
The inflammatory caspases (caspase-1, -4 and -5) are potential therapeutic targets for autoimmune and inflammatory diseases due to their involvement in the immune response upon inflammasome formation. A series of small molecules based on the 4-(piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine scaffold were synthesized with varying substituents on the piperazine ring. Several compounds were pan-selective inhibitors of the inflammatory caspases, caspase-1, -4 and -5, with the ethylbenzene derivative CK-1-41 displaying low nanomolar Ki values across this family of caspases...
October 12, 2016: Bioorganic & Medicinal Chemistry Letters
Rong Li, Xiaoxia Yang, Yan Yu, Meilan Zhou, Xiujuan Tian, Shidong Feng, Hanmin Wang
Objective To explore the role of the anti-inflammatory cytokine C1q/tumor necrosis factor related protein 6 (CTRP6) in gentamicin-induced acute kidney injury in rats. Methods SD rats were divided into 5 groups including control group, model group and the other 3 experimental groups. The rats in model group and experimental groups were subcutaneously injected with gentamicin at the dose of 400 mg/(kg.d) for consecutive 2 days to induce acute renal injury. Two days before gentamicin injection, the rats in the 3 experimental groups were given pAd-CTRP6 at the doses of 0...
November 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
Lili Duan, Zidong Liu, Lin Wang, Binfang Ma, Yibing Fan, Ying Xu, Fenfen Guo
Objective To explore the effect of C1q/tumor necrosis factor related protein 4 (CTRP4) on the placental trophoblasts of preeclampsia model rats. Methods Placental trophoblastic tissues were respectively collected from normal pregnant rats and model rats with preeclampsia, and then mRNA and protein expression levels of CTRP4, interleukin 1β (IL-1β), and caspase-1 were detected with quantitative real-time PCR (qRT-PCR) and Western blotting. Primary placental trophoblasts were isolated from normal pregnant rats and model rats; at different time points, flow cytometry was used to detect the number of PI(+)caspase-1(+) pyroptotic cells; and qRT-PCR and Western blotting were used to detect expression levels of IL-1β and caspase-1...
November 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
Qian Sun, Patricia Loughran, Richard Shapiro, Indira H Shrivastava, Daniel J Antoine, Tunliang Li, Zhengzheng Yan, Jie Fan, Timothy R Billiar, Melanie J Scott
: Sterile liver inflammation, such as liver ischemia reperfusion, hemorrhagic shock after trauma and drug-induced liver injury is initiated and regulated by endogenous mediators including DNA and reactive oxygen species. Here we identify a novel mechanism for redox-mediated regulation of AIM2-inflammasome activation in hepatocytes after redox stress in mice, which occurs via interaction with cytosolic HMGB1. We show that in liver during hemorrhagic shock in mice, and in hepatocytes after hypoxia with reoxygenation, cytosolic HMGB1 associates with AIM2 and is required for activation of caspase-1 in response to cytosolic DNA...
October 24, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Jing Qiu, Min Wang, Jun Zhang, Qing Cai, Dan Lu, Yansong Li, Yushu Dong, Tianzhi Zhao, Huisheng Chen
Neuroinflammation remains the primary cause of morbidity and mortality in stroke-induced secondary brain injury. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is involved in diverse inflammatory diseases, including cerebral ischemia, and is thus considered an effective therapeutic target. In the present study, we investigated the neuroprotection of Sinomenine (SINO), a potent natural anti-apoptotic and anti-inflammatory molecule, against cerebral ischemia in a mouse model of middle cerebral artery occlusion (MCAO) in vivo and in an oxygen glucose deprivation (OGD)-treated astrocytes/microglia model in vitro...
October 18, 2016: International Immunopharmacology
Fabian Treude, Tobias Gladbach, Jacqueline Plaster, Jörg Hartkamp
Aberrant histone deacetylase (HDAC) activity often correlates with neoplastic transformation and inhibition of HDACs by small molecules has emerged as a promising strategy to treat hematological malignancies in particular. Treatment with HDAC inhibitors (HDACis) often prompts tumor cells to undergo apoptosis, thereby causing a caspase-dependent cleavage of target proteins. An unexpectedly large number of proteins are in vivo caspase substrates and defining caspase-mediated substrate specificity is a major challenge...
2017: Methods in Molecular Biology
Florian Hoss, Juan F Rodriguez-Alcazar, Eicke Latz
The inflammasome adapter ASC links activated inflammasome sensors to the effector molecule pro-caspase-1. Recruitment of pro-caspase-1 to ASC promotes the autocatalytic activation of caspase-1, which leads to the release of pro-inflammatory cytokines, such as IL-1β. Upon triggering of inflammasome sensors, ASC assembles into large helical fibrils that interact with each other serving as a supramolecular signaling platform termed the ASC speck. Alternative splicing, post-translational modifications of ASC, as well as interaction with other proteins can perturb ASC function...
October 19, 2016: Cellular and Molecular Life Sciences: CMLS
C-M Chu, K-C Kao, S-H Huang, D-Y Chuang, H-P Wu
Severe sepsis is associated with significant mortality and massive immune cell lose, or apoptosis. It is unclear whether plasma apoptosis biomarkers could be used as a diagnostic test for severe sepsis. Forty patients with severe sepsis and 35 healthy controls were enrolled. The percentage and apoptosis of monocytes and lymphocytes were detected by flow cytometric analysis. Plasma levels of tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR), soluble Fas (sFas), Fas ligand (FasL), caspase-1, and procalcitonin (PCT) were measured...
September 30, 2016: Cellular and Molecular Biology
Encheng Yang, Xiao Li, Ningyi Jin
AIM: This study was aimed to evaluate the therapeutic efficiency of a non-virus based specific chimeric multi-domain DNA transferred with apoptin in human hepatocellular carcinoma (HCC) HepG-2 cells in vitro and in mice H22 cells in vivo. METHODS: We firstly constructed the multi-domain recombinant chimeric proteins based on recombinant proteins [G (yeast GAL4), NG (none GAL4), TG (GAL4 + Tat protein) and TNG (Tat protein)] and pUAS-Apoptin plasmid, and transfected them into human HepG-2 cells...
2016: Cancer Cell International
Andrea Villar-Lorenzo, Alejandro E Ardiles, Ana I Arroba, Enrique Hernández-Jiménez, Virginia Pardo, Eduardo López-Collazo, Ignacio A Jiménez, Isabel L Bazzochi, Águeda González-Rodríguez, Ángela M Valverde
A series of 31 pentacyclic triterpenoids isolated from the root barks of Celastrus vulcanicola and Maytenus jelskii were tested for cytotoxicity and inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 18 (C18) and 25 (C25) exhibited significant inhibition of LPS-induced NO release at 50 and 25μM concentrations, respectively, and decreased mRNAs of pro-inflammatory cytokines. At the molecular level, C18 neither inhibited LPS-mediated phosphorylation of mitogen activated protein kinases (MAPKs) nor nuclear translocation of nuclear factor kappa beta (NFκB)...
October 14, 2016: Toxicology and Applied Pharmacology
Christian Adam, Jonas Wohlfarth, Maike Haußmann, Helga Sennefelder, Annette Rodin, Mareike Maler, Stefan F Martin, Matthias Goebeler, Marc Schmidt
Chromium allergy is a common occupational skin disease mediated by chromium (VI)-specific T cells that induce delayed-type hypersensitivity in sensitized individuals. Additionally, chromium (VI) can act as irritant. Both responses critically require innate immune activation, but if and how chromium (VI) elicits this signal is currently unclear.Using human monocytes, primary human keratinocytes and murine dendritic cells we show that chromium (VI) compounds fail to trigger direct proinflammatory activation but potently induce processing and secretion of IL-1β...
October 14, 2016: Journal of Investigative Dermatology
Olivier Huet, Raelene J Pickering, Chris Tikellis, Celine Latouche, Fenella Long, Bronwyn Kingwell, Bryan Dickinson, Chris J Chang, Seth Masters, Fabienne Mackay, Mark E Cooper, Judy B de Haan
OBJECTIVES: To study the effect of a lack of antioxidant defenses during lethal pneumonia induced by Klebsiella pneumonia, compared to wild-type mice. SETTING: Laboratory experiments. SUBJECTS: C57Bl6 and glutathione peroxidase 1 knockout mice. INTERVENTION: Murine acute pneumonia model induced by Klebsiella pneumonia. MEASUREMENTS AND MAIN RESULTS: We show here that despite a lack of one of the major antioxidant defense enzymes, glutathione peroxidase 1 knockout mice are protected during lethal pneumonia induced by Klebsiella pneumonia, compared to wild-type mice...
October 3, 2016: Critical Care Medicine
Kai-Chih Hung, Hui-Ju Huang, Yi-Ting Wang, Anya Maan-Yuh Lin
ETHNOPHARMACOLOGICAL RELEVANCE: Neuroinflammation, oxidative stress, and protein aggregation form a vicious cycle in the pathophysiology of Parkinson's disease (PD); activated microglia is the main location of neuroinflammation. A Chinese medicine book, "Shanghan Lun", known as the "Treatises on Cold damage Diseases" has suggested that Scutellaria baicalensis Georgi is effective in treating CNS diseases. The anti-inflammatory mechanisms of baicalein, a phenolic flavonoid in the dried root of Scutellaria baicalensis Georgi, remain to be explored...
October 11, 2016: Journal of Ethnopharmacology
Ashley A Basiorka, Kathy L McGraw, Erika A Eksioglu, Xianghong Chen, Joseph Johnson, Ling Zhang, Qing Zhang, Brittany A Irvine, Thomas Cluzeau, David A Sallman, Eric Padron, Rami Komrokji, Lubomir Sokol, Rebecca C Coll, Avril A B Robertson, Matthew A Cooper, John L Cleveland, Luke A O'Neill, Sheng Wei, Alan F List
Despite genetic heterogeneity, myelodysplastic syndromes (MDS) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDS is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem/progenitor cells (HSPC) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of IL-1β and IL-18 and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPC and bone marrow plasma...
October 13, 2016: Blood
Laura Schoenlaub, Rama Cherla, Yan Zhang, Guoquan Zhang
Our recent study demonstrated that virulent Coxiella burnetii Nine Mile phase I (NMI) is capable of infecting and replicating within peritoneal B1a cells and that B1a cells play an important role in host defense against C. burnetii infection in mice. However, it remains unknown if avirulent Nine Mile phase II (NMII) can infect and replicate in B1a cells and whether NMI and NMII can differentially interact with B1a cells. In this study, we examined if NMI and NMII can differentially modulate host cell apoptotic signaling in B1a cells...
October 10, 2016: Infection and Immunity
Amir S Yazdi, Kamran Ghoreschi
The interleukin-1 (IL-1) family consists of several pro- or anti-inflammatory proteins, with pro-inflammatory IL-1β being its best characterized member. IL-1β is one of the most prominent mediators of inflammation resulting in fever and immune activation via binding to IL-1 receptor 1. Due to its potency, its secretion is tightly regulated. First the transcription of the biologically inactive proform is induced by TLR activation, TNF, or IL-1 receptor activation by mature IL-1α or IL-1β. For the secretion of IL-1β, inflammasome activation as second stimulus is needed...
2016: Advances in Experimental Medicine and Biology
Peipei Zhang, Kohsuke Tsuchiya, Takeshi Kinoshita, Hiroko Kushiyama, Sofya Suidasari, Mizuki Hatakeyama, Hisanori Imura, Norihisa Kato, Takashi Suda
Vitamin B6 includes six water-soluble vitamers: pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN), and their phosphorylated forms. Pyridoxal 5'-phosphate (PLP) is an important cofactor for many metabolic enzymes. Several lines of evidence demonstrate that blood levels of PLP are significantly lower in patients with inflammation than in control subjects, and that vitamin B6 has anti-inflammatory effects, with therapeutic potential for a variety of inflammatory diseases. Although one of our group (NK) previously demonstrated that PL inhibits the NF-κB pathway, the molecular mechanism by which vitamin B6 suppresses inflammation is not well understood...
October 12, 2016: Journal of Biological Chemistry
M B Huante, S Gupta, V C Calderon, S J Koo, M Sinha, B A Luxon, N J Garg, J J Endsley
Pathogens frequently exploit or evade inflammasome activation in order to survive and proliferate. Alternatively, inadequate inflammasome activation by attenuated microorganisms or adjuvanted subunit vaccines may contribute to poor longevity of protection. To further understand these pathways, we determined the differential inflammasome transcriptome of human THP monocyte-derived macrophages in response to Mycobacterium bovis BCG, as compared to LPS or Trypanosoma cruzi. The results identify the highly specific innate recognition programs associated with inflammasome activation by human macrophages exposed to these microbial stimuli...
September 28, 2016: Tuberculosis
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