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https://www.readbyqxmd.com/read/28301594/daxx-plays-a-novel-role-in-t-cell-survival-but-is-dispensable-in-fas-induced-apoptosis
#1
Jinghe Li, Liangyue Qian, John P Dowling, Christine Curcione, Drishya Kurup, Jianke Zhang
Daxx was originally isolated as a Fas-binding protein. However, the in vivo function of Daxx in Fas-induced apoptosis has remained enigmatic. Fas plays an important role in homeostasis in the immune system. Fas gene mutations lead to autoimmune-lymphoproliferation (lpr) diseases characterized by hyperplasia of secondary lymphoid organs. It is well established that the FADD adaptor binds to Fas, and recruits/activates caspase 8. However, additional proteins including Daxx have also been indicated to associate with Fas...
2017: PloS One
https://www.readbyqxmd.com/read/28291695/structure-based-drug-design-of-novel-ask1-inhibitors-using-an-integrated-lead-optimization-strategy
#2
Tony S Gibson, Benjamin Johnson, Andrea Fanjul, Petro Halkowycz, Douglas R Dougan, Derek Cole, Steven Swann
Structure-based drug design is an iterative process that is an established means to accelerate lead optimization, and is most powerful when integrated with information from different sources. Herein is described the use of such methods in conjunction with deconstruction and re-optimization of a diverse series of ASK1 chemotypes along with high-throughput screening that lead to the identification of a novel series of efficient ASK1 inhibitors displaying robust MAP3K pathway inhibition.
March 2, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28288548/upregulated-glutathione-transferase-omega-1-correlates-with-progression-of-urinary-bladder-carcinoma
#3
Tatjana Djukic, Tatjana Simic, Marija Pljesa-Ercegovac, Marija Matic, Sonja Suvakov, Vesna Coric, Dejan Dragicevic, Ana Savic-Radojevic
OBJECTIVES: Newly discovered glutathione transferase omega 1 (GSTO1-1) plays an important role in the glutathionylation cycle, a significant mechanism of protein function regulation. GSTO1-1 expression pattern has not been studied in transitional cell carcinoma (TCC), as yet. METHODS: A total of 56 TCC tumor and corresponding non-tumor specimens were investigated. Glutathione content and thioltransferase activity were measured spectrophotometrically. Protein-glutathione mixed disulfides were measured fluorimetrically...
March 13, 2017: Redox Report: Communications in Free Radical Research
https://www.readbyqxmd.com/read/28284893/gstm1-genotype-is-an-independent-prognostic-factor-in-clear-cell-renal-cell-carcinoma
#4
Vesna M Coric, Tatjana P Simic, Tatjana D Pekmezovic, Gordana M Basta-Jovanovic, Ana R Savic-Radojevic, Sanja M Radojevic-Skodric, Marija G Matic, Sonja R Suvakov, Dejan P Dragicevic, Tanja M Radic, Zoran M Dzamic, Marija S Pljesa-Ercegovac
PURPOSE: Owing to dual functionality of cytosolic glutathione S-transferases (GSTs), they might affect both the development and the progression of renal cell carcinoma (RCC). However, the data on the prognostic value of GST polymorphism in patients with RCC are scarce. Hence, we evaluated the effect of GST gene variants on both the risk of RCC development and the postoperative prognosis in patients with clear cell RCC (ccRCC). METHODS: GST genotypes were determined in 305 patients with RCC and 326 matched controls, whereas the overall survival was evaluated in patients with ccRCC only...
March 8, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28254824/stressed-platelets-ask1-for-a-mapk
#5
Robert Flaumenhaft
No abstract text is available yet for this article.
March 2, 2017: Blood
https://www.readbyqxmd.com/read/28243335/the-epstein-barr-virus-encoded-mir-bart22-targets-map3k5-to-promote-host-cell-proliferative-and-invasive-abilities-in-nasopharyngeal-carcinoma
#6
Ruichao Chen, Minfeng Zhang, Qiulian Li, Hanzhen Xiong, Shaoyan Liu, Weiyi Fang, Qianbing Zhang, Zhen Liu, Xuehu Xu, Qingping Jiang
miR-BART22, a new discovered Epstein-Barr virus (EBV) miRNA, is abundant in Nasopharyngeal carcinoma (NPC). It has been reported that miR-BART22 promoted the tumor development by down-modulating EBV LMP2 expression to evade the host immune response. But its cell target genes have still been obscure. We have reported an inverse correlation between the BART-22 and MAP3K5 protein expression in NPC tissues and NPC cell lines. Meanwhile, MAP3K5 protein expression level was significantly decreased in primary NPC tissues compared with nasopharyngitis when MAP3K5 mRNA expression was consistent in two group tissues...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28242696/structural-basis-of-autoregulatory-scaffolding-by-apoptosis-signal-regulating-kinase-1
#7
Johannes F Weijman, Abhishek Kumar, Sam A Jamieson, Chontelle M King, Tom T Caradoc-Davies, Elizabeth C Ledgerwood, James M Murphy, Peter D Mace
Apoptosis signal-regulating kinases (ASK1-3) are apical kinases of the p38 and JNK MAP kinase pathways. They are activated by diverse stress stimuli, including reactive oxygen species, cytokines, and osmotic stress; however, a molecular understanding of how ASK proteins are controlled remains obscure. Here, we report a biochemical analysis of the ASK1 kinase domain in conjunction with its N-terminal thioredoxin-binding domain, along with a central regulatory region that links the two. We show that in solution the central regulatory region mediates a compact arrangement of the kinase and thioredoxin-binding domains and the central regulatory region actively primes MKK6, a key ASK1 substrate, for phosphorylation...
February 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28219095/kaempferol-attenuates-cardiac-hypertrophy-via-regulation-of-ask1-mapk-signaling-pathway-and-oxidative-stress
#8
Hong Feng, Jianlei Cao, Guangyu Zhang, Yanggan Wang
Kaempferol has been demonstrated to provide benefits for the treatment of atherosclerosis, coronary heart disease, hyperlipidemia, and diabetes through its antioxidant and anti-inflammatory properties. However, its role in cardiac hypertrophy remains to be elucidated. The aim of our study was to investigate the effects of kaempferol on cardiac hypertrophy and the underlying mechanism. Mice subjected to aorta banding were treated with or without kaempferol (100 mg/kg/d, p. o.) for 6 weeks. Echocardiography was performed to evaluate cardiac function...
February 20, 2017: Planta Medica
https://www.readbyqxmd.com/read/28218919/targeting-casp8-and-fadd-like-apoptosis-regulator-ameliorates-nonalcoholic-steatohepatitis-in-mice-and-nonhuman-primates
#9
Pi-Xiao Wang, Yan-Xiao Ji, Xiao-Jing Zhang, Ling-Ping Zhao, Zhen-Zhen Yan, Peng Zhang, Li-Jun Shen, Xia Yang, Jing Fang, Song Tian, Xue-Yong Zhu, Jun Gong, Xin Zhang, Qiao-Fang Wei, Yong Wang, Jing Li, Lu Wan, Qingguo Xie, Zhi-Gang She, Zhihua Wang, Zan Huang, Hongliang Li
Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1)...
February 20, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28210980/molecular-mechanisms-of-ire1%C3%AE-ask1-pathway-reactions-to-unfolded-protein-response-in-drn-neurons-of-post-traumatic-stress-disorder-rats
#10
Fanzhen Kong, Fang Han, Yanhao Xu, Yuxiu Shi
The goal of this study was to further elucidate the molecular mechanisms of post-traumatic stress disorder (PTSD) pathogenesis and to provide experimental evidence for new drug targets for effective PTSD treatment. Expression changes of IRE1α, ASK1, and other downstream molecules of the IRE1α-ASK1 endoplasmic reticulum stress (ERS) signaling pathway were investigated. JNK, P38, CHOP, Bcl-2, and Bax were analyzed at both protein and mRNA levels of dorsal raphe nucleus (DRN) neurons of PTSD rats. The rat PTSD model was established via the single-prolonged stress (SPS) method...
April 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28195154/zinc-finger-protein-zpr9-functions-as-an-activator-of-ampk-related-serine-threonine-kinase-mpk38-melk-involved-in-ask1-tgf-%C3%AE-p53-signaling-pathways
#11
Hyun-A Seong, Ravi Manoharan, Hyunjung Ha
Murine protein serine-threonine kinase 38 (MPK38), an AMP-activated protein kinase (AMPK)-related kinase, has been implicated in the induction of apoptosis signal-regulating kinase 1 (ASK1)-, transforming growth factor-β (TGF-β)-, and p53-mediated activity involved in metabolic homeostasis. Here, zinc finger protein ZPR9 was found to be an activator of MPK38. The association of MPK38 and ZPR9 was mediated by cysteine residues present in each of these two proteins, Cys(269) and Cys(286) of MPK38 and Cys(305) and Cys(308) of ZPR9...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28119399/an-als-associated-mutant-sod1-rapidly-suppresses-kcnt1-slack-na-activated-k-channels-in-aplysia-neurons
#12
Yalan Zhang, Weiming Ni, Arthur L Horwich, Leonard K Kaczmarek
Mutations that alter levels of Slack (KCNT1) Na(+)-activated K(+) current produce devastating effects on neuronal development and neuronal function. We now find that Slack currents are rapidly suppressed by oligomers of mutant human Cu/Zn superoxide dismutase 1 (SOD1), which are associated with motor neuron toxicity in an inherited form of amyotrophic lateral sclerosis (ALS). We recorded from bag cell neurons of Aplysia californica, a model system to study neuronal excitability. We found that injection of fluorescent wild-type SOD1 (wt SOD1YFP) or monomeric mutant G85R SOD1YFP had no effect on net ionic currents measured under voltage clamp...
February 22, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28045936/detoxification-of-mitochondrial-oxidants-and-apoptotic-signaling-are-facilitated-by-thioredoxin-2-and-peroxiredoxin-3-during-hyperoxic-injury
#13
Benjamin J Forred, Darwin R Daugaard, Brianna K Titus, Ryan R Wood, Miranda J Floen, Michelle L Booze, Peter F Vitiello
Mitochondria play a fundamental role in the regulation of cell death during accumulation of oxidants. High concentrations of atmospheric oxygen (hyperoxia), used clinically to treat tissue hypoxia in premature newborns, is known to elicit oxidative stress and mitochondrial injury to pulmonary epithelial cells. A consequence of oxidative stress in mitochondria is the accumulation of peroxides which are detoxified by the dedicated mitochondrial thioredoxin system. This system is comprised of the oxidoreductase activities of peroxiredoxin-3 (Prx3), thioredoxin-2 (Trx2), and thioredoxin reductase-2 (TrxR2)...
2017: PloS One
https://www.readbyqxmd.com/read/28043644/differential-expression-of-survival-proteins-during-decreased-intracellular-oxygen-tension-in-brain-endothelial-cells-of-grey-mullets
#14
Padmini Ekambaram, Meenakshi Narayanan, Parimala Parasuraman
The brain requires constant oxygen supply to perform its biological functions essential for survival. Because of low oxygen capacity and poor oxygen diffusibility of water, many fish species have evolved various adaptive mechanisms to cope with depleted oxygen. Endothelial cells (EC) are the primary components responsible for controlled environment of brain. Brain homeostasis largely depends on integrity of the EC. To elucidate their adaptive strategy, EC were isolated from the fish brain of Kovalam-control site and Ennore estuary-test/field hypoxic site and were subjected to low oxygen tension in laboratory...
December 30, 2016: Marine Pollution Bulletin
https://www.readbyqxmd.com/read/28040492/valproic-acid-and-ask1-deficiency-ameliorate-optic-neuritis-and-neurodegeneration-in-an-animal-model-of-multiple-sclerosis
#15
Yuriko Azuchi, Atsuko Kimura, Xiaoli Guo, Goichi Akiyama, Takahiko Noro, Chikako Harada, Atsuko Nishigaki, Kazuhiko Namekata, Takayuki Harada
Optic neuritis, which is an acute inflammatory demyelinating syndrome of the central nervous system, is one of the major complications in multiple sclerosis (MS). Herein, we investigated the therapeutic potential of valproic acid (VPA) on optic neuritis in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. EAE was induced in C57BL/6 mice by immunization with MOG35-55 and VPA (300mg/kg) was administered via intraperitoneal injection once daily from day 3 postimmunization until the end of the experimental period (day 28)...
February 3, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28039481/phosphorylation-of-eb1-regulates-the-recruitment-of-clip-170-and-p150glued-to-the-plus-ends-of-astral-microtubules
#16
Jie Ran, Youguang Luo, Yijun Zhang, Yang Yang, Miao Chen, Min Liu, Dengwen Li, Jun Zhou
Phosphorylation of end-binding protein 1 (EB1), a key member of microtubule plus end-tracking proteins (+TIPs), by apoptosis signal-regulating kinase 1 (ASK1) has been demonstrated to promote the stability of astral microtubules during mitosis by stimulating the binding of EB1 to microtubule plus ends. However, the roles of other members of the +TIPs family in ASK1/EB1-mediated regulation of astral microtubules are unknown. Herein, we show that ASK1-mediated phosphorylation of EB1 enhances the localization of cytoplasmic linker protein 170 (CLIP-170) and p150glued to the plus ends of astral microtubules...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28031524/adenosine-5-monophosphate-blocks-acetaminophen-toxicity-by-increasing-ubiquitination-mediated-ask1-degradation
#17
Xiao Yang, Yibei Zhan, Qi Sun, Xi Xu, Yi Kong, Jianfa Zhang
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure in the world. Hepatic c-jun NH2-terminal protein kinase (JNK) activation is thought to be a consequence of oxidative stress produced during APAP metabolism. Activation of JNK signals causes hepatocellular damage with necrotic and apoptotic cell death. Here we found that APAP caused a feedback increase in plasma adenosine 5'-monophsphate (5'-AMP). We demonstrated that co-administration of APAP and 5'-AMP significantly ameliorated APAP-induced hepatotoxicity in mice, without influences on APAP metabolism and its analgesic function...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28028021/ask1-regulates-platelet-granule-secretion-thromboxane-a2-generation-and-thrombus-formation-in-mice
#18
Meghna U Naik, Pravin Patel, Randall Derstine, Ramya Turaga, Xi Chen, Kalyan Golla, Keith B Neeves, Hidenori Ichijo, Ulhas P Naik
Mitogen activated protein kinases (MAPKs) are expressed in platelets and are activated downstream of physiological agonists. Pharmacological and genetic evidence indicate that MAPKs play a significant role in hemostasis and thrombosis, but it is not well understood how MAPKs are activated upon platelet stimulation. Here, we show that Apoptosis Signal-regulating Kinase 1 (ASK1), a member of the MAP3K family, is expressed in both human and murine platelets. ASK1 is rapidly and robustly activated upon platelet stimulation by physiological agonists...
December 27, 2016: Blood
https://www.readbyqxmd.com/read/27989136/dynamic-phosphorylation-of-apoptosis-signal-regulating-kinase-1-ask1-in-response-to-oxidative-and-electrophilic-stress
#19
Carlos Morales Betanzos, Joel D Federspiel, Amy M Palubinsky, BethAnn McLaughlin, Daniel C Liebler
Apoptosis signal-regulating kinase 1 (ASK1) is a critical cellular stress sensor that senses diverse reactive chemotypes and integrates these chemical signals into a single biological pathway response. It is unknown whether ASK1 senses all stressors in the same way or if unique stress-specific mechanisms detect distinct chemotypes. In order to answer this question, we treated ASK1-expressing cells with two distinct stress activators, H2O2 and 4-hydroxy-2-nonenal (HNE), and monitored the phosphorylation state of ASK1...
December 19, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27942664/phenolics-extracted-from-tartary-fagopyrum-tartaricum-l-gaerth-buckwheat-bran-exhibit-antioxidant-activity-and-an-antiproliferative-effect-on-human-breast-cancer-mda-mb-231-cells-through-the-p38-map-kinase-pathway
#20
Fuhua Li, Xiaoli Zhang, Yao Li, Keke Lu, Ran Yin, Jian Ming
Phenolics extracted from tartary buckwheat (Fagopyrum tartaricum L. Gaerth) bran were analyzed quantitatively and qualitatively. The bioactivity of the phenolic extracts was evaluated, such as the antioxidant activity, and the inhibition capacity on the growth of cancer cells. The molecular mechanism for the inhibitive effect on cancer cells was explored. Results indicated that tartary buckwheat bran phenolics mainly exist in a free form, and free phenolics were twice as abundant as bound phenolics. Free caffeic acid (119...
December 12, 2016: Food & Function
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