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https://www.readbyqxmd.com/read/29775996/interplay-between-adenylate-metabolizing-enzymes-and-amp-activated-protein-kinase
#1
REVIEW
Marcella Camici, Simone Allegrini, Maria Grazia Tozzi
Purine nucleotides are involved in a variety of cellular functions, such as energy storage and transfer, and signalling, in addition to being the precursors of nucleic acids and cofactors of many biochemical reactions. They can be generated through two separate pathways, the de novo biosynthesis pathway and the salvage pathway. De novo purine biosynthesis leads to the formation of IMP, from which the adenylate and guanylate pools are generated by two additional steps. The salvage pathways utilize hypoxanthine, guanine and adenine to generate the corresponding mononucleotides...
May 18, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29775963/brain-ischemic-preconditioning-protects-against-ischemic-injury-and-preserves-the-blood-brain-barrier-via-oxidative-signaling-and-nrf2-activation
#2
Tuo Yang, Yang Sun, Leilei Mao, Meijuan Zhang, Qianqian Li, Lili Zhang, Yejie Shi, Rehana K Leak, Jun Chen, Feng Zhang
Brain ischemic preconditioning (IPC) with mild ischemic episodes is well known to protect the brain against subsequent ischemic challenges. However, the underlying mechanisms are poorly understood. Here we demonstrate the critical role of the master redox transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), in IPC-mediated neuroprotection and blood-brain barrier (BBB) preservation. We report that IPC causes generation of endogenous lipid electrophiles, including 4-hydroxy-2-nonenal (4-HNE), which release Nrf2 from inhibition by Keap1 (via Keap1-C288) and inhibition by glycogen synthase kinase 3β (via GSK3β-C199)...
May 6, 2018: Redox Biology
https://www.readbyqxmd.com/read/29775946/il-9-exhibits-elevated-expression-in-osteonecrosis-of-femoral-head-patients-and-promotes-cartilage-degradation-through-activation-of-jak-stat-signaling-in-vitro
#3
Wei Geng, Wen Zhang, Jinzhu Ma
Osteonecrosis of the femoral head (ONFH) often causes severe symptoms in young people and limits the mobility of the hip joint. Interleukin-9 (IL-9) is a multi-functional inflammatory factor that participates in lumbar disk herniation and arthritis and has been reported in many studies. However, the correlation between IL-9 and ONFH is unclear. The present study aimed to determine the role of IL-9 in the pathogenetic mechanism of osteonecrosis. To assess IL-9 expression in ONFH and femoral neck fracture patients, cartilage tissue was examined through western blot analysis and immunohistochemistry...
May 15, 2018: International Immunopharmacology
https://www.readbyqxmd.com/read/29775935/design-synthesis-antiproliferative-activity-and-docking-studies-of-quinazoline-derivatives-bearing-2-3-dihydro-indole-or-1-2-3-4-tetrahydroquinoline-as-potential-egfr-inhibitors
#4
Yiqiang OuYang, Wensheng Zou, Liang Peng, Zunhua Yang, Qidong Tang, Mengzi Chen, Shuang Jia, Hong Zhang, Zhou Lan, Pengwu Zheng, Wufu Zhu
Eight series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and PC-3). Most of the forty nine target compounds showed excellent antiproliferative activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, MCF-7 and PC-3 cancer cell lines, with the IC50 values of 1.09 ± 0.04 μM, 1.34 ± 0.13 μM and 1.23 ± 0...
May 9, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29775809/transient-asymptomatic-pulmonary-opacities-during-osimertinib-treatment-and-its-clinical-implication
#5
Hansang Lee, Ho Yun Lee, Jong-Mu Sun, Se-Hoon Lee, Youjin Kim, Song Ee Park, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
INTRODUCTION: Osimertinib is an oral, potent, irreversible 3rd generation EGFR tyrosine kinase inhibitor (TKI) approved for the treatment of T790M positive non-small cell lung cancer (NSCLC) patients who failed 1st or 2nd generation EGFR TKIs. Interstitial lung disease (ILD) is a rare complication with osimertinib, occurring in 1-3%. Recently, relatively high incidence of transient asymptomatic pulmonary opacities (TAPOs) which are different from ILD has been described. However, its clinical implication has not been fully determined yet...
May 15, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29775761/the-bone-anabolic-effects-of-irisin-are-through-preferential-stimulation-of-aerobic-glycolysis
#6
Dingdong Zhang, ChuHyun Bae, Junghak Lee, Jiho Lee, Zeyu Jin, Myeongmo Kang, Young Suk Cho, Jeong-Han Kim, Weontae Lee, Sung-Kil Lim
Irisin, a recently identified hormone secreted by skeletal muscle in response to exercise, exhibits anabolic effects on the skeleton primarily through the stimulation of bone formation. However, the mechanism underlying the irisin-stimulated anabolic response remains largely unknown. To uncover the underlying mechanism, we biosynthesized recombinant irisin (r-irisin) using an Escherichia coli expression system and used it to treat several osteoblast cell types. Our synthesized r-irisin could promote proliferation and differentiation of osteoblasts as evidenced by enhanced expression of osteoblast-specific transcriptional factors, including Runt-related transcription factor-2 (Runx2), Oster (Osx), as well as early osteoblastic differentiation markers such as alkaline phosphatase (Alp) and collagen type I alpha 1 (Col1a1)...
May 15, 2018: Bone
https://www.readbyqxmd.com/read/29775756/pkm2-a-potential-target-for-regulating-cancer
#7
REVIEW
Yu-Huan Li, Xiao-Feng Li, Jia-Tao Liu, Hua Wang, Lu-Lu Fan, Jun Li, Guo-Ping Sun
Aberrated glucose metabolism is a key future of cancer cells. Unlike normal cells, tumor cells favor glycolysis even in the presence of sufficient oxygen. Pyruvate kinase (PK), a key glucose metabolic enzyme, converts phosphoenolpyruvate (PEP) to pyruvate by transferring the high-energy phosphate group to adenosine diphosphate (ADP) to produce adenosine triphosphate (ATP). Pyruvate kinase M2 (PKM2), one of the four isozyme of PK, which universally expressed in rapidly proliferating cells such as embryonic cells and cancer cells...
May 15, 2018: Gene
https://www.readbyqxmd.com/read/29775750/the-effects-of-capn1-gene-inactivation-on-the-differential-expression-of-genes-in-skeletal-muscle
#8
William T Olive, Brittney N Keel, Amanda K Lindholm-Perry, Justyna Horodyska, Andrew P Foote
Protein turnover is required for muscle growth and regeneration and several proteolytic enzymes, including the calpains, degrade myofibrillar proteins during this process. In a previous experiment, phenotypic differences were observed between μ-calpain knockout (KO) and wild type (WT) mice, including nutrient accretion and fiber type differences. These changes were particularly evident as the animals aged. Thus, we utilized 18 mice (9 KO and 9 WT) to compare transcript abundance to identify differentially expressed genes (DEGs) at 52 wk of age...
May 15, 2018: Gene
https://www.readbyqxmd.com/read/29775743/redox-regulation-of-protein-kinase-c-by-selenometabolites-and-selenoprotein-thioredoxin-reductase-limits-cancer-prevention-by-selenium
#9
REVIEW
Rayudu Gopalakrishna, Usha Gundimeda, Sarah Zhou, Bui Helena, Arne Holmgren
The cancer-preventive mechanism of selenium should address the way low concentrations of selenometabolites react with cellular targets without being diffused from the sites of generation, the way selenium selectively kills tumor cells, and the intriguing U-shaped curve that is seen with dietary supplementation of selenium and cancer prevention. Protein kinase C (PKC), a receptor for tumor promoters, is well suited for this mechanism. Due to the catalytic redox cycle, low concentrations of methylselenol, a postulated active metabolite of selenium, react with the tumor-promoting lipid hydroperoxide bound to PKC to form methylseleninic acid (MSA), which selectively reacts with thiol residues present within the vicinity of the PKC catalytic domain to inactivate it...
May 15, 2018: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29775701/lithium-posttreatment-alleviates-blood-brain-barrier-injury-after-intracerebral-hemorrhage-in-rats
#10
Weishan Li, Rui Li, Sha Zhao, Cheng Jiang, Zhen Liu, Xiaobo Tang
Vasogenic cerebral edema formation after blood brain barrier (BBB) damage aggravates the devastating consequences of intracerebral hemorrhage (ICH). The present study aims to probe into a therapeutic method on BBB preservation after ICH with a glycogen synthase kinase-3β (GSK-3β) inhibitor, lithium. Intrastriatal infusion of semicoagulated autologous whole blood or sham surgery was performed on male Sprague-Dawley (SD) rats (n = 208).Experimental animals received administration of 4,6-disubstitutedpyrrolo-pyrimidine (TWS119), lithium alone or in combination with a phosphatidylinositol 3-kinase inhibitor, wortmannin, after ICH...
May 15, 2018: Neuroscience
https://www.readbyqxmd.com/read/29775660/the-role-of-the-egfr-signaling-pathway-in-stem-cell-differentiation-during-planarian-regeneration-and-homeostasis
#11
REVIEW
Sara Barberán, Francesc Cebrià
Cell signaling is essential for cells to adequately respond to their environment. One of the most evolutionarily conserved signaling pathways is that of the epidermal growth factor receptor (EGFR). Transmembrane receptors with intracellular tyrosine kinase activity are activated by the binding of their corresponding ligands. This in turn activates a wide variety of intracellular cascades and induces the up- or downregulation of target genes, leading to a specific cellular response. Freshwater planarians are an excellent model in which to study the role of cell signaling in the context of stem-cell based regeneration...
May 15, 2018: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/29775632/controlled-delivery-of-a-focal-adhesion-kinase-inhibitor-results-in-accelerated-wound-closure-with-decreased-scar-formation
#12
Kun Ma, Sun Hyung Kwon, Jagannath Padmanabhan, Dominik Duscher, Artem A Trotsyuk, Yixiao Dong, Mohammed Inayathullah, Jayakumar Rajadas, Geoffrey C Gurtner
Formation of scars following wounding or trauma represents a significant healthcare burden costing the economy billions of dollars every year. Activation of focal adhesion kinase (FAK) has been shown to play a pivotal role in transducing mechanical signals to elicit fibrotic responses and scar formation during wound repair. We have previously shown that inhibition of FAK using local injections of a small molecule FAK inhibitor (FAKI) can attenuate scar development in a hypertrophic scar model. Clinical translation of FAKI therapy has been challenging, however, due to the lack of an effective drug delivery system for extensive burn injuries, blast injuries, and large excisional injuries...
May 15, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29775584/conformational-activation-of-argonaute-by-distinct-yet-coordinated-actions-of-the-hsp70-and-hsp90-chaperone-systems
#13
Kotaro Tsuboyama, Hisashi Tadakuma, Yukihide Tomari
Loading of small RNAs into Argonaute, the core protein in RNA silencing, requires the Hsp70/Hsp90 chaperone machinery. This machinery also activates many other clients, including steroid hormone receptors and kinases, but how their structures change during chaperone-dependent activation remains unclear. Here, we utilized single-molecule Förster resonance energy transfer (smFRET) to probe the conformational changes of Drosophila Ago2 mediated by the chaperone machinery. We found that empty Ago2 exists in various closed conformations...
May 17, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29775492/a-mitogen-activated-protein-kinase-phosphatase-influences-grain-size-and-weight-in-rice
#14
Ran Xu, Haiyue Yu, Junmin Wang, Penggen Duan, Baolan Zhang, Jing Li, Yu Li, Jinsong Xu, Jia Lyu, Na Li, Tuanyao Chai, Yunhai Li
Grain size and weight are directly associated with grain yield in crops. However, the molecular mechanisms that set final grain size and weight remain largely unknown. Here, we characterize two large grain mutants, large grain8-1 (large8-1) and large grain8-2 (large8-2). LARGE8 encodes the mitogen-activated protein kinase phosphatase1 (OsMKP1). Loss of function mutations in OsMKP1 results in large grains, while overexpression of OsMKP1 leads to small grains. OsMKP1 determines grain size by restricting cell proliferation in grain hulls...
May 18, 2018: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/29775479/acute-intermittent-hypoxia-and-rehabilitative-training-following-cervical-spinal-injury-alters-neuronal-hypoxia-and-plasticity-associated-protein-expression
#15
Atiq Hassan, Breanna M Arnold, Sally Caine, Behzad M Toosi, Valerie M K Verge, Gillian D Muir
One of the most promising approaches to improve recovery after spinal cord injury (SCI) is the augmentation of spontaneously occurring plasticity in uninjured neural pathways. Acute intermittent hypoxia (AIH, brief exposures to reduced O2 levels alternating with normal O2 levels) initiates plasticity in respiratory systems and has been shown to improve recovery in respiratory and non-respiratory spinal systems after SCI in experimental animals and humans. Although the mechanism by which AIH elicits its effects after SCI are not well understood, AIH is known to alter protein expression in spinal neurons in uninjured animals...
2018: PloS One
https://www.readbyqxmd.com/read/29775417/targeting-histone-methyltransferase-enhancer-of-zeste-homolog-2-inhibits-renal-epithelial-mesenchymal-transition-and-attenuates-renal-fibrosis
#16
Xiaoxu Zhou, Chongxiang Xiong, Evelyn Tolbert, Ting C Zhao, George Bayliss, Shougang Zhuang
Enhancer of zeste homolog-2 (EZH2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. Its role in renal epithelial-mesenchymal transition (EMT) remains unknown. In this study, we found that EZH2 and H3K27me3 were highly expressed in mouse kidney with unilateral ureteral obstruction and cultured mouse kidney proximal tubular (TKPT) cells undergoing EMT. Inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) attenuated renal fibrosis, which was associated with preserving E-cadherin expression and inhibiting Vimentin up-regulation in the obstructed kidney...
May 18, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29775409/transactivation-domain-of-p53-regulates-dna-repair-and-integrity-in-human-ips-cells
#17
Ramaswamy Kannappan, Saidulu Mattapally, Pooja A Wagle, Jianyi Zhang
The role of p53 transactivation domain (p53-TAD), a multifunctional and dynamic domain, on DNA repair and retaining DNA integrity in human iPS cells has never been studied. p53-TAD was knocked out in iPS cells using CRISPR/Cas9 and was confirmed by DNA sequencing. p53-TAD KO cells were characterized by: accelerated proliferation, decreased population doubling time, and unaltered Bcl2, BBC3, IGF1R, Bax and altered Mdm2, p21, and PIDD transcripts expression. In p53-TAD KO cells p53 regulated DNA repair proteins XPA, DNA polH and DDB2 expression were found to be reduced compared to p53-WT cells...
May 18, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29775397/receptor-tyrosine-kinase-signaling-in-cancer-radiotherapy-and-its-targeting-for-tumor-radiosensitization
#18
Poushali Bhattacharya, Neena G Shetake, Badri N Pandey, Amit Kumar
PURPOSE: One of the most important implications of 'Radiation Biology' research is to improve cancer radiotherapy with minimum side effects. In this regard, combination of chemotherapy with radiation has significantly improved tumor control as well as overall survival in a variety of cancers. However, this has been achieved at the cost of significant normal tissue toxicity, due to the lack of specificity of chemotherapy. Membrane-localized receptor tyrosine kinases (RTKs) have been found to play a driving role in various hallmarks of cancer...
May 18, 2018: International Journal of Radiation Biology
https://www.readbyqxmd.com/read/29775310/fragment-based-discovery-of-a-potent-orally-bioavailable-inhibitor-which-modulates-the-phosphorylation-and-catalytic-activity-of-erk1-2
#19
Tom D Heightman, Valerio Berdini, Hannah Braithwaite, Ildiko Maria Buck, Megan Cassidy, Juan Castro, Aurelie Courtin, James E H Day, Charlotte East, Lynsey Fazal, Brent Graham, Charlotte M Griffiths-Jones, John F Lyons, Vanessa Martins, Sandra Muench, Joanne M Munck, David Norton, Marc O'Reilly, Nick Palmer, Puja Pathuri, Michael Reader, David C Rees, Sharna J Rich, Caroline Richardson, Harpreet Saini, Neil T Thompson, Nicola G Wallis, Hugh Walton, Nicola E Wilsher, Alison J-A Woolford, Michael Cooke, David Cousin, Stuart Onions, Jonathan Shannon, John Watts, Christopher W Murray
Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signalling through ERK1/2. Here we describe the fragment based generation of ERK1/2 inhibitors which block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29775287/computational-prediction-and-analysis-for-tyrosine-post-translational-modifications-via-elastic-net
#20
Man Cao, Guodong Chen, Lina Wang, Pingping Wen, Shaoping Shi
The tyrosine residue has been identified as suffering three major post-translational modifications (PTMs) including nitration, sulfation, and phosphorylation, which could be involved in different physiological and pathological processes. Multiple tyrosine residues of the whole protein may be modified concurrently, where PTM of a single tyrosine may affect modification of other neighboring tyrosine residues. Hence, it is significant and beneficial to predict nitration, sulfation, and phosphorylation of tyrosine residues in the whole protein sequence...
May 18, 2018: Journal of Chemical Information and Modeling
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