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https://www.readbyqxmd.com/read/28430817/kaposi-sarcoma-herpesvirus-kshv-latency-associated-nuclear-antigen-lana-recruits-components-of-the-mrn-mre11-rad50-nbs1-repair-complex-to-modulate-an-innate-immune-signaling-pathway-and-viral-latency
#1
Giuseppe Mariggiò, Sandra Koch, Guigen Zhang, Magdalena Weidner-Glunde, Jessica Rückert, Semra Kati, Susann Santag, Thomas F Schulz
Kaposi Sarcoma Herpesvirus (KSHV), a γ2-herpesvirus and class 1 carcinogen, is responsible for at least three human malignancies: Kaposi Sarcoma (KS), Primary Effusion Lymphoma (PEL) and Multicentric Castleman's Disease (MCD). Its major nuclear latency protein, LANA, is indispensable for the maintenance and replication of latent viral DNA in infected cells. Although LANA is mainly a nuclear protein, cytoplasmic isoforms of LANA exist and can act as antagonists of the cytoplasmic DNA sensor, cGAS. Here, we show that cytosolic LANA also recruits members of the MRN (Mre11-Rad50-NBS1) repair complex in the cytosol and thereby inhibits their recently reported role in the sensing of cytoplasmic DNA and activation of the NF-κB pathway...
April 21, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28423586/the-role-of-ros-and-subsequent-dna-damage-response-in-puma-induced-apoptosis-of-ovarian-cancer-cells
#2
Jun Yang, Xinyu Zhao, Mei Tang, Lei Li, Yi Lei, Ping Cheng, Wenhao Guo, Yu Zheng, Wei Wang, Na Luo, Yong Peng, Aiping Tong, Yuquan Wei, Chunlai Nie, Zhu Yuan
PUMA is a member of the "BH3-only" branch of the BCL-2 family. Our previous study suggests a therapeutic potential of PUMA in treating ovarian cancer, however, the action mechanism of PUMA remains elusive. In this work, we found that in PUMA adenovirus-infected A2780s ovarian cancer cells, exogenous PUMA was partially accumulated in the cytosol and mainly located to the mitochondria. We further showed that PUMA induces mitochondrial dysfunction-mediated apoptosis and ROS generation through functional BAX in a ROS generating enzyme- and caspase-independent manner irrespective of their p53 status, and results in activation of Nrf2/HO-1 pathway...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423339/germ-cell-specific-inflammasome-component-nlrp14-negatively-regulates-cytosolic-nucleic-acid-sensing-to-promote-fertilization
#3
Takayuki Abe, Albert Lee, Ramaswami Sitharam, Jordan Kesner, Raul Rabadan, Sagi D Shapira
Cytosolic sensing of nucleic acids initiates tightly regulated programs to limit infection. Oocyte fertilization represents a scenario wherein inappropriate responses to exogenous yet non-pathogen-derived nucleic acids would have negative consequences. We hypothesized that germ cells express negative regulators of nucleic acid sensing (NAS) in steady state and applied an integrated data-mining and functional genomics approach to identify a rheostat of DNA and RNA sensing-the inflammasome component NLRP14. We demonstrated that NLRP14 interacted physically with the nucleic acid sensing pathway and targeted TBK1 (TANK binding kinase 1) for ubiquitination and degradation...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28422993/th17-micro-milieu-regulates-nlrp1-dependent-caspase-5-activity-in-skin-autoinflammation
#4
Stephanie Zwicker, Eva Hattinger, Daniela Bureik, Aleksandra Batycka-Baran, Andreas Schmidt, Peter-Arne Gerber, Simon Rothenfusser, Michel Gilliet, Thomas Ruzicka, Ronald Wolf
IL-1β is a potent player in cutaneous inflammation and central for the development of a Th17 micro-milieu in autoinflammatory diseases including psoriasis. Its production is controlled at the transcriptional level and by subsequent posttranslational processing via inflammatory caspases. In this study, we detected inflammatory caspase-5 active in epidermal keratinocytes and in psoriatic skin lesions. Further, interferon-γ and interleukin-17A synergistically induced caspase-5 expression in cultured keratinocytes, which was dependent on the antimicrobial peptide psoriasin (S100A7)...
2017: PloS One
https://www.readbyqxmd.com/read/28422568/cgas-sting-tbk1-irf3-7-induced-interferon-%C3%AE-contributes-to-the-clearing-of-non-tuberculous-mycobacterial-infection-in-mice
#5
Nanthapon Ruangkiattikul, Andreas Nerlich, Ketema Abdissa, Stefan Lienenklaus, Abdulhadi Suwandi, Nina Janze, Kristin Laarmann, Julia Spanier, Ulrich Kalinke, Siegfried Weiss, Ralph Goethe
Type I interferons (IFN-I), such as IFN-α and IFN-β are important messengers in the host response against bacterial infections. Knowledge about the role of IFN-I in infections by nontuberculous mycobacteria (NTM) is limited. Here we show that macrophages infected with pathogens of the Mycobacterium avium complex produced significantly lower amounts of IFN-β than macrophages infected with the opportunistic pathogen M. smegmatis. To dissect the molecular mechanisms of this phenomenon, we focussed on the obligate pathogen Mycobacterium avium ssp...
April 19, 2017: Virulence
https://www.readbyqxmd.com/read/28419846/bit1-regulates-cell-migration-and-survival-in-oral-squamous-cell%C3%A2-carcinoma
#6
Yan Xiao, Yanjie Yang, Jing Wang, Wenlu Li
PURPOSE: Increasing evidence has shown that Bcl-2 inhibitor of transcription 1 (Bit1) involves a variety of biological processes in the process of tumor development and progression. We hypothesized that Bit1 would be overexpressed in oral squamous cell carcinoma (OSCC); therefore, we examined Bit1 gene expression and protein production, as well as explored the effect of elevated Bit1 levels on OSCC cells. MATERIALS AND METHODS: We investigated the use of quantitative real-time reverse transcription-polymerase chain reaction and immunohistochemistry analysis for Bit1 messenger RNA and protein levels...
March 23, 2017: Journal of Oral and Maxillofacial Surgery
https://www.readbyqxmd.com/read/28416447/evolutionary-origins-of-cgas-sting-signaling
#7
REVIEW
Shally R Margolis, Stephen C Wilson, Russell E Vance
Detection of foreign nucleic acids is an important strategy for innate immune recognition of pathogens. In vertebrates, pathogen-derived DNA is sensed in the cytosol by cGAS, which produces the cyclic dinucleotide (CDN) second messenger cGAMP to activate the signaling adaptor STING. While induction of antiviral type I interferons (IFNs) is the major outcome of STING activation in vertebrates, it has recently become clear that core components of the cGAS-STING pathway evolved more than 600 million years ago, predating the evolution of type I IFNs...
April 14, 2017: Trends in Immunology
https://www.readbyqxmd.com/read/28415024/glucocorticoids-differentially-regulate-the-innate-immune-responses-of-tlr4-and-the-cytosolic-dna-sensing-pathway
#8
Jinli Wang, Ruining Wang, Jiahui Yang, Xiaofan Yang, Shengfeng Hu, Hui Wang, Chaoying Zhou, Wenjing Xiong, Qian Wen, Li Ma
Glucocorticoids (GCs) are widely used to treat the chronic inflammatory disorders because of their powerful anti-inflammatory properties; however, their effects on macrophage-mediated immune responses are not completely understood. In the present study, we found that GCs decreased LPS-mediated TBK1 activation and the expression of IFN-β, RANTES and CXCL-10; however, poly(dA:dT)-induced TBK1 activity and cytokine expression were not affected by GCs treatment. Furthermore, GCs decreased the expression of key autophagy-related genes (ATGs), including ATG5, ATG7 and ATG12, and inhibited autophagy in macrophages after LPS stimulation...
April 14, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28409562/chemotherapy-induced-intestinal-inflammatory-responses-are-mediated-by-exosome-secretion-of-double-strand-dna-via-aim2-inflammasome-activation
#9
Qiaoshi Lian, Jun Xu, Shanshan Yan, Min Huang, Honghua Ding, Xiaoyu Sun, Aiwei Bi, Jian Ding, Bing Sun, Meiyu Geng
Chemotherapies are known often to induce severe gastrointestinal tract toxicity but the underlying mechanism remains unclear. This study considers the widely applied cytotoxic agent irinotecan (CPT-11) as a representative agent and demonstrates that treatment induces massive release of double-strand DNA from the intestine that accounts for the dose-limiting intestinal toxicity of the compound. Specifically, "self-DNA" released through exosome secretion enters the cytosol of innate immune cells and activates the AIM2 (absent in melanoma 2) inflammasome...
April 14, 2017: Cell Research
https://www.readbyqxmd.com/read/28400561/a-hybrid-stochastic-model-of-folate-mediated-one-carbon-metabolism-effect-of-the-common-c677t-mthfr-variant-on-de-novo-thymidylate-biosynthesis
#10
Karla Misselbeck, Luca Marchetti, Martha S Field, Marco Scotti, Corrado Priami, Patrick J Stover
Folate-mediated one-carbon metabolism (FOCM) is an interconnected network of metabolic pathways, including those required for the de novo synthesis of dTMP and purine nucleotides and for remethylation of homocysteine to methionine. Mouse models of folate-responsive neural tube defects (NTDs) indicate that impaired de novo thymidylate (dTMP) synthesis through changes in SHMT expression is causative in folate-responsive NTDs. We have created a hybrid computational model comprised of ordinary differential equations and stochastic simulation...
April 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28400476/gad1-upregulation-programs-aggressive-features-of-cancer-cell-metabolism-in-the-brain-metastatic-microenvironment
#11
Patricia M Schnepp, Dennis D Lee, Ian H Guldner, Treasa K O'Tighearnaigh, Erin N Howe, Bhavana Palakurthi, Kaitlyn E Eckert, Tiffany A Toni, Brandon L Ashfeld, Siyuan Zhang
The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downegulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells...
April 11, 2017: Cancer Research
https://www.readbyqxmd.com/read/28399655/cyclic-gmp-amp-as-an-endogenous-second-messenger-in-innate-immune-signaling-by-cytosolic-dna
#12
Kazuki Kato, Hiroki Omura, Ryuichiro Ishitani, Osamu Nureki
The innate immune system functions as the first line of defense against invading bacteria and viruses. In this context, the cGAS/STING [cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase/ STING] signaling axis perceives the nonself DNA associated with bacterial and viral infections, as well as the leakage of self DNA by cellular dysfunction and stresses, to elicit the host's immune responses. In this pathway, the noncanonical cyclic dinucleotide 2',3'-cyclicGMP-AMP(2',3'-cGAMP) functions as a second messenger for signal transduction: 2',3'-cGAMP is produced by the enzyme cGAS upon its recognition of double-stranded DNA, and then the 2',3'-cGAMP is recognized by the receptor STING to induce the phosphorylation of downstream factors, including TBK1 (TANK binding kinase 1) and IRF3 (interferon regulatory factor 3)...
April 7, 2017: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/28390674/cytotoxic-effects-of-cadmium-and-zinc-co-exposure-in-pc12%C3%A2-cells-and-the-underlying-mechanism
#13
Md Mostafizur Rahman, Junki Ukiana, Rachael Uson-Lopez, Md Tajuddin Sikder, Takeshi Saito, Masaaki Kurasaki
Cadmium (Cd(2+)) is a well studied inducer of cellular necrosis and apoptosis. Zinc (Zn(2+)) is known to inhibit apoptosis induced by toxicants including Cd(2+) both in vitro and in vivo. The mechanism of Zn(2+)-mediated protection from Cd(2+)-induced cytotoxicity is not established. In this study, we aimed to understand the effects of Zn(2+) on Cd(2+)-induced cytotoxicity and apoptosis using PC12 cells. Cell viability and DNA fragmentation assays in PC12 cells exposed to Cd(2+) and/or Zn(2+) revealed that Cd(2+) (5 and 10 μmol/L) alone induced significant cell death, and co-exposure to Zn(2+) (5, 10, and 100 μmol/L) for 48 h had a protective effect...
May 1, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28381880/20s-immunoproteasomes-remove-formaldehyde-damaged-cytoplasmic-proteins-suppressing-caspase-independent-cell-death
#14
Sara Ortega-Atienza, Casey Krawic, Lauren Watts, Caitlin McCarthy, Michal W Luczak, Anatoly Zhitkovich
Immunoproteasomes are known for their involvement in antigen presentation. However, their broad tissue presence and other evidence are indicative of nonimmune functions. We examined a role for immunoproteasomes in cellular responses to the endogenous and environmental carcinogen formaldehyde (FA) that binds to cytosolic and nuclear proteins producing proteotoxic stress and genotoxic DNA-histone crosslinks. We found that immunoproteasomes were important for suppression of a caspase-independent cell death and the long-term survival of FA-treated cells...
April 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28380257/tdp-43-and-fus-en-route-from-the-nucleus-to-the-cytoplasm
#15
REVIEW
Helena Ederle, Dorothee Dormann
Misfolded or mislocalized RNA-binding proteins (RBPs) and, consequently, altered mRNA processing, can cause neuronal dysfunction, eventually leading to neurodegeneration. Two prominent examples are the RBPs TAR DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS), which form pathological messenger ribonucleoprotein aggregates in patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative disorders. Here, we review the multiple functions of TDP-43 and FUS in mRNA processing, both in the nucleus and in the cytoplasm...
April 5, 2017: FEBS Letters
https://www.readbyqxmd.com/read/28373600/the-age-and-sex-specific-decline-of-the-20s-proteasome-and-the-nrf2-cncc-signal-transduction-pathway-in-adaption-and-resistance-to-oxidative-stress-in-drosophila-melanogaster
#16
Laura C D Pomatto, Sarah Wong, Caroline Carney, Brenda Shen, John Tower, Kelvin J A Davies
Hallmarks of aging include loss of protein homeostasis and dysregulation of stress-adaptive pathways. Loss of adaptive homeostasis, increases accumulation of DNA, protein, and lipid damage. During acute stress, the Cnc-C (Drosophila Nrf2 orthologue) transcriptionally-regulated 20S proteasome degrades damaged proteins in an ATP-independent manner. Exposure to very low, non-toxic, signaling concentrations of the redox-signaling agent hydrogen peroxide (H2O2) cause adaptive increases in the de novo expression and proteolytic activity/capacity of the 20S proteasome in female D...
April 3, 2017: Aging
https://www.readbyqxmd.com/read/28373432/myricetin-induces-apoptosis-of-human-anaplastic-thyroid-cancer-cells-via-mitochondria-dysfunction
#17
Sunhyo Jo, Tae Kwun Ha, Sang-Hun Han, Mi Eun Kim, Inae Jung, Hee-Woo Lee, Sung Kwon Bae, Jun Sik Lee
AIM: Thyroid cancer is the most common endocrine malignancy, with an increasing incidence worldwide. Most thyroid cancers are well differentiated and have a favorable outcome. However, undifferentiated thyroid cancers are one of the most lethal human malignancies. Anaplastic thyroid cancer (ATC) accounts for 2% of all thyroid cancers, and its median survival rate is low. ATC is responsible for more than one-third of thyroid cancer-related deaths. Myricetin is a flavonol compound found in walnuts, herbs, and various berries and is known to induce apoptotic death of various types of cancer cells...
April 2017: Anticancer Research
https://www.readbyqxmd.com/read/28366989/black-soybean-seed-coat-polyphenols-prevent-aaph-induced-oxidative-dna-damage-in-hepg2-cells
#18
Yasukiyo Yoshioka, Xiu Li, Tianshun Zhang, Takakazu Mitani, Michiko Yasuda, Fumio Nanba, Toshiya Toda, Yoko Yamashita, Hitoshi Ashida
Black soybean seed coat extract (BE), which contains abundant polyphenols such as procyanidins, cyanidin 3-glucoside, (+)-catechin, and (-)-epicatechin, has been reported on health beneficial functions such as antioxidant activity, anti-inflammatory, anti-obesity, and anti-diabetic activities. In this study, we investigated that prevention of BE and its polyphenols on 2,2'-azobis(2-methylpropionamide) dihydrochloride (AAPH)-induced oxidative DNA damage, and found that these polyphenols inhibited AAPH-induced formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a biomarker for oxidative DNA damage in HepG2 cells...
March 2017: Journal of Clinical Biochemistry and Nutrition
https://www.readbyqxmd.com/read/28365246/the-association-between-oxidative-stress-induced-galectins-and-differentiation-of-human-promyelocytic-hl-60-cells
#19
James R Vinnai, Robert C Cumming, Graham J Thompson, Alexander V Timoshenko
Galectins are multifunctional β-galactoside-binding proteins that are involved in the regulation of cellular stress responses and differentiation. The relationship between these processes is unclear and we report here that galectins display oxidative-stress specific expression patterns in neutrophil-like differentiated HL-60 cells. Three galectins (-1, -3, and -10) are upregulated in response to either menadione or DMSO exposure whereas galectins -9 and -12 exhibited a stimulus-dependent downregulation. Changes in galectin expression are oxidant dependent based on the observations that 1) oxidative stress biomarkers HMOX1 (heme oxygenase-1) and NCF1 (neutrophil cytosolic factor 1, which is also a biomarker of neutrophil differentiation) are elevated in both cases, and 2) the antioxidant N-acetyl-L-cysteine restores basal expression of galectin-3 following oxidant exposure...
March 30, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28363908/nonspecific-dna-binding-of-cgas-n-terminus-promotes-cgas-activation
#20
Jianli Tao, Xiao-Wei Zhang, Jianshi Jin, Xiao-Xia Du, Tengfei Lian, Jing Yang, Xiang Zhou, Zhengfan Jiang, Xiao-Dong Su
The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) mediates innate immune responses against invading pathogens, or against self-dsDNA, which causes autoimmune disorders. Upon nonspecific binding of cytosolic B-form DNA, cGAS synthesizes the second messenger 2'3'-cGAMP and triggers STING-dependent signaling to produce type I IFNs. The cGAS comprises less-conserved N-terminal residues and highly conserved nucleotidyltransferase/Mab21 domains. The function and structure of the well-conserved domains have been extensively studied, whereas the physiological function of the N-terminal domain of cGAS is largely uncharacterized...
March 31, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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