682 results on '"Enzymes -- Regulation"'
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2. Study Results from Brown University Update Understanding of Cholangiocarcinoma (Elevated 2-oxoglutarate Antagonizes Dna Damage Responses In Cholangiocarcinoma Chemotherapy Through Regulating Aspartate Beta-hydroxylase)
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Oncology, Experimental ,Hydroxylases -- Health aspects ,Enzymes -- Regulation ,Chemotherapy -- Methods ,Organic acids -- Health aspects ,DNA damage -- Research ,Cancer -- Chemotherapy -- Research ,Health - Abstract
2024 JAN 20 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators publish new report on Oncology - Cholangiocarcinoma. According to news reporting [...]
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- 2024
3. Data on Peroxisome Proliferator-Activated Receptors Reported by Researchers at High Point University (Ppar Beta/delta Agonism With Gw501516 Increases Myotube Pgc-1 Alpha Content and Reduces Bcaa Media Content Independent of Changes In Bcaa ...)
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Enzymes -- Regulation ,Branched chain amino acids -- Health aspects -- Physiological aspects ,Amino acid metabolism -- Research ,Diabetes -- Research ,Type 2 diabetes -- Development and progression -- Care and treatment ,Health - Abstract
2023 JUL 22 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Data detailed on Proteins - Peroxisome Proliferator-Activated Receptors have been presented. According [...]
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- 2023
4. Research from University of Surrey Provides New Data on Biosensors [Dysregulated NAD(H) homeostasis associated with ciprofloxacin tolerance in Escherichia coli investigated on a single-cell level with the Peredox [NADH:NAD+] biosensor]
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Biosensors -- Usage ,Enzymes -- Regulation ,Drug resistance in microorganisms -- Research ,Homeostasis -- Research ,NAD (Coenzyme) -- Physiological aspects ,Microbiological research ,Ciprofloxacin -- Physiological aspects ,Escherichia coli -- Physiological aspects ,Health - Abstract
2023 JUL 8 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Research findings on biosensors are discussed in a new report. According to [...]
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- 2023
5. Reports from Johns Hopkins University Provide New Insights into Extracellular Matrix Proteins (Lysyl Oxidase-like 2 Processing By Factor Xa Modulates Its Activity and Substrate Preference)
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Medical research ,Medicine, Experimental ,Enzymes -- Regulation ,Oxidases -- Chemical properties -- Physiological aspects -- Health aspects ,Substrates (Biochemistry) -- Health aspects -- Physiological aspects ,Health - Abstract
2023 JUN 24 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Current study results on Proteins - Extracellular Matrix Proteins have been published. [...]
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- 2023
6. Kuwait University Researcher Has Published New Study Findings on Hypertension (Novel regulatory role of post-translational structural modification in modulating Src kinase activity in pulmonary arterial hypertension)
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Post-translational modification -- Research ,Enzymes -- Regulation ,Protein kinases -- Health aspects ,Pulmonary hypertension -- Development and progression ,Health - Abstract
2023 JUN 17 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators publish new report on hypertension. According to news originating from Kuwait [...]
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- 2023
7. Investigators from University of California San Francisco (UCSF) Target Heparin Therapy [Heparin Does Not Regulate Circulating Human Pcsk9 (Proprotein Convertase Subtilisin-kexin Type 9) In a General Population-brief Report]
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Heparin -- Health aspects -- Physiological aspects ,Liver cells -- Health aspects -- Physiological aspects ,Enzymes -- Regulation ,Molecular chaperones -- Health aspects -- Physiological aspects ,Health - Abstract
2023 APR 8 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Current study results on Drugs and Therapies - Heparin Therapy have been [...]
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- 2023
8. Reports Summarize Chemicals and Chemistry Findings from Wesleyan University (Network Analysis of Molecular Dynamics Sectors In the P53 Protein)
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Molecular dynamics -- Analysis ,Tumor proteins -- Models -- Physiological aspects ,Enzymes -- Regulation ,Pharmaceutical chemistry -- Methods ,Health - Abstract
2023 FEB 4 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Research findings on Chemicals and Chemistry are discussed in a new report. [...]
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- 2023
9. New Nucleoproteins Data Have Been Reported by Researchers at Sao Paulo State University (UNESP) [Optimization of Resveratrol Used as a Scaffold to Design Histone Deacetylase (HDAC-1 and HDAC-2) Inhibitors]
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Drugs -- Structure-activity relationships ,Enzymes -- Regulation ,Structure-activity relationship (Pharmacology) -- Testing ,Resveratrol -- Health aspects ,Health - Abstract
2022 NOV 12 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Researchers detail new data in nucleoproteins. According to news reporting from Araraquara, [...]
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- 2022
10. Findings from Wuhan University Yields New Data on Allergic Rhinitis (Downregulation of Deubiquitinating Enzyme Usp25 Promotes the Development of Allergic Rhinitis By Enhancing Tslp Signaling In the Nasal Epithelium)
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Epithelium -- Genetic aspects -- Health aspects ,Medical research ,Medicine, Experimental ,Hay-fever -- Development and progression -- Genetic aspects ,Proteases -- Genetic aspects -- Health aspects ,Enzymes -- Regulation ,Cellular signal transduction -- Research ,Health - Abstract
2022 NOV 12 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Researchers detail new data in Immune System Diseases and Conditions - Allergic [...]
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- 2022
11. Protective effect of pycnogenol against gamma radiation-induced lung injury in rat: DNA damage, lipid peroxidation, antioxidant levels, and histopathological changes
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Tan, Fazile, Yay, Arzu, Yildiz, Oguz, and Kaan, Dilek
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Lung diseases -- Genetic aspects -- Development and progression -- Care and treatment ,Enzymes -- Regulation ,DNA damage -- Health aspects ,Health - Abstract
Byline: Fazile. Tan, Arzu. YAY, Oguz. Yildiz, Dilek. Kaan Background and Objective: The study aims to evaluate the histopathological changes, enzymatic alterations, and DNA damage in rat lungs induced by [...]
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- 2022
12. Studies from Novo-Nordisk A/S Have Provided New Information about Anxiolytics Sedatives and Hypnotics (In Vitro Cyp450 Enzyme Downregulation By Glp-1/glucagon Coagonist Does Not Translate To Observed Drug-drug Interactions In the Clinic)
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Enzymes -- Regulation ,Drug interactions -- Analysis ,Peptides -- Chemical properties -- Health aspects ,Health - Abstract
2022 SEP 10 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- A new study on Drugs and Therapies - Anxiolytics Sedatives and Hypnotics [...]
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- 2022
13. Research Data from Beckman Research Institute at the City of Hope Update Understanding of Life Science (The Beginning of Gpx2 and 30 Years Later)
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Free radicals (Chemistry) -- Health aspects ,Gene expression -- Health aspects ,Enzymes -- Regulation ,Peroxidase -- Health aspects ,Health - Abstract
2022 AUG 27 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- A new study on Life Science is now available. According to news [...]
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- 2022
14. H. Lee Moffitt Cancer Center Researchers Describe Advances in Cancer (Proton export upregulates aerobic glycolysis)
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Oncology, Experimental ,Biological transport -- Health aspects ,Enzymes -- Regulation ,Protons -- Health aspects -- Physiological aspects ,Cancer -- Development and progression -- Genetic aspects -- Physiological aspects -- Research ,Glycolysis -- Research -- Health aspects ,Health - Abstract
2022 AUG 6 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- New research on cancer is the subject of a new report. According [...]
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- 2022
15. Researchers from Icahn School of Medicine at Mount Sinai Discuss Findings in Solid Cancer (Effect of Concurrent Beta-blocker Use In Patients Receiving Immune Checkpoint Inhibitors for Advanced Solid Tumors)
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Oncology, Experimental ,Adrenergic mechanisms -- Health aspects ,Enzymes -- Regulation ,Cancer -- Care and treatment -- Research ,Health - Abstract
2022 JUL 30 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- New research on Oncology - Solid Cancer is the subject of a [...]
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- 2022
16. Study Findings on Autism Discussed by Researchers at Universitat Basel (How Is CYP17A1 Activity Altered in Autism? A Pilot Study to Identify Potential Pharmacological Targets)
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Enzymes -- Regulation ,Pharmacology, Experimental ,Cytochrome P-450 -- Health aspects -- Measurement -- Physiological aspects ,Autism -- Drug therapy -- Physiological aspects ,Health - Abstract
2022 JUL 16 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- New research on autism is the subject of a new report. According [...]
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- 2022
17. Low-barrier hydrogen bonds in enzyme cooperativity
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Dai, Shaobo, Funk, Lisa-Marie, von Pappenheim, Fabian Rabe, Sautner, Viktor, Paulikat, Mirko, Schröder, Benjamin, and Uranga, Jon
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Enzymes -- Regulation ,Hydrogen bonding -- Analysis ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
The underlying molecular mechanisms of cooperativity and allosteric regulation are well understood for many proteins, with haemoglobin and aspartate transcarbamoylase serving as prototypical examples.sup.1,2. The binding of effectors typically causes a structural transition of the protein that is propagated through signalling pathways to remote sites and involves marked changes on the tertiary and sometimes even the quaternary level.sup.1-5. However, the origin of these signals and the molecular mechanism of long-range signalling at an atomic level remain unclear.sup.5-8. The different spatial scales and timescales in signalling pathways render experimental observation challenging; in particular, the positions and movement of mobile protons cannot be visualized by current methods of structural analysis. Here we report the experimental observation of fluctuating low-barrier hydrogen bonds as switching elements in cooperativity pathways of multimeric enzymes. We have observed these low-barrier hydrogen bonds in ultra-high-resolution X-ray crystallographic structures of two multimeric enzymes, and have validated their assignment using computational calculations. Catalytic events at the active sites switch between low-barrier hydrogen bonds and ordinary hydrogen bonds in a circuit that consists of acidic side chains and water molecules, transmitting a signal through the collective repositioning of protons by behaving as an atomistic Newton's cradle. The resulting communication synchronizes catalysis in the oligomer. Our studies provide several lines of evidence and a working model for not only the existence of low-barrier hydrogen bonds in proteins, but also a connection to enzyme cooperativity. This finding suggests new principles of drug and enzyme design, in which sequences of residues can be purposefully included to enable long-range communication and thus the regulation of engineered biomolecules. Structural and biophysical studies reveal that low-barrier hydrogen bonds enable long-range communication between the active sites of multimeric enzymes and synchronise catalysis., Author(s): Shaobo Dai [sup.1] [sup.2] , Lisa-Marie Funk [sup.1] [sup.2] , Fabian Rabe von Pappenheim [sup.1] [sup.2] , Viktor Sautner [sup.1] [sup.2] , Mirko Paulikat [sup.3] , Benjamin Schröder [sup.3] [...]
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- 2019
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18. Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth
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Fontan, Lorena, Qiao, Qi, Hatcher, John M., Casalena, Gabriella, Us, Ilkay, Teater, Matt, Durant, Matt, Du, Guangyan, Xia, Min, Bilchuk, Natalia, Chennamadhavuni, Spandan, Palladino, Giuseppe, Inghirami, Giorgio, Philippar, Ulrike, Wu, Hao, Scott, David A., Gray, Nathanael S., and Melnick, Ari
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Enzymes -- Regulation ,Lymphomas -- Genetic aspects -- Development and progression -- Care and treatment ,Health care industry - Abstract
The paracaspase MALT1 plays an essential role in activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) downstream of B cell and TLR pathway genes mutated in these tumors. Although MALT1 is considered a compelling therapeutic target, the development of tractable and specific MALT1 protease inhibitors has thus far been elusive. Here, we developed a target engagement assay that provides a quantitative readout for specific MALT1- inhibitory effects in living cells. This enabled a structure-guided medicinal chemistry effort culminating in the discovery of pharmacologically tractable, irreversible substrate-mimetic compounds that bind the MALT1 active site. We confirmed that MALT1 targeting with compound 3 is effective at suppressing ABC DLBCL cells in vitro and in vivo. We show that a reduction in serum IL-10 levels exquisitely correlates with the drug pharmacokinetics and degree of MALT1 inhibition in vitro and in vivo and could constitute a useful pharmacodynamic biomarker to evaluate these compounds in clinical trials. Compound 3 revealed insights into the biology of MALT1 in ABC DLBCL, such as the role of MALT1 in driving JAK/STAT signaling and suppressing the type I IFN response and MHC class II expression, suggesting that MALT1 inhibition could prime lymphomas for immune recognition by cytotoxic immune cells., Introduction Diffuse large B cell lymphoma (DLBCL) is the most common subtype of B cell non-Hodgkin lymphoma (1). Gene expression profiling enabled the subclassification of DLBCLs into distinct molecular subtypes, [...]
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- 2018
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19. Recent Studies from Institute for Clinical and Experimental Medicine Add New Data to Heart Failure (Pulmonary Vasculature Responsiveness to Phosphodiesterase-5A Inhibition in Heart Failure With Reduced Ejection Fraction: Possible Role of Plasma ...)
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Enzymes -- Regulation ,Heart failure -- Development and progression -- Care and treatment ,Health - Abstract
2022 JUN 25 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators discuss new findings in heart failure. According to news originating from [...]
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- 2022
20. University of Agriculture Researcher Reports Recent Findings in Toxicology Research (Isorhamnetin: a flavonoid, attenuated doxorubicin-induced testicular injury via regulation of steroidogenic enzymes and apoptotic signaling gene expression in ...)
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Enzymes -- Regulation ,Bioflavonoids -- Health aspects ,Flavones -- Health aspects ,Pharmacology, Experimental ,Oxidoreductases -- Health aspects ,Flavonoids -- Health aspects ,Doxorubicin -- Complications and side effects ,Health - Abstract
2022 JUN 11 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- New study results on toxicology research have been published. According to news [...]
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- 2022
21. Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation
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Xiang, Jin, Chen, Chang, Liu, Rui, Gou, Dongmei, Chang, Lei, Deng, Haijun, Gao, Qingzhu, Zhang, Wanjun, Tuo, Lin, Pan, Xuanming, Liang, Li, Xia, Jie, Huang, Luyi, Yao, Ke, Wang, Bohong, Hu, Zeping, Huang, Ailong, Wang, Kai, and Tang, Ni
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Enzymes -- Regulation ,Phosphotransferases -- Health aspects ,Glucose metabolism -- Genetic aspects -- Health aspects ,Hepatoma -- Genetic aspects -- Development and progression -- Care and treatment ,Health care industry - Abstract
Although cancer cells are frequently faced with a nutrient- and oxygen-poor microenvironment, elevated hexosaminebiosynthesis pathway (HBP) activity and protein O-GlcNAcylation (a nutrient sensor) contribute to rapid growth of tumor and are emerging hallmarks of cancer. Inhibiting O-GlcNAcylation could be a promising anticancer strategy. The gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) is downregulated in hepatocellular carcinoma (HCC). However, little is known about the potential role of PCK1 in enhanced HBP activity and HCC carcinogenesis under glucose-limited conditions. In this study, PCK1 knockout markedly enhanced the global O-GlcNAcylation levels under low-glucose conditions. Mechanistically, metabolic reprogramming in PCK1-loss hepatoma cells led to oxaloacetate accumulation and increased de novo uridine triphosphate synthesis contributing to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis. Meanwhile, deletion of PCK1 also resulted in AMPK-GFAT1 axis inactivation, promoting UDP-GlcNAc synthesis for elevated OGlcNAcylation. Notably, lower expression of PCK1 promoted CHK2 threonine 378 O-GlcNAcylation, counteracting its stability and dimer formation, increasing CHK2-dependent Rb phosphorylation and HCC cell proliferation. Moreover, aminooxyacetic acid hemihydrochloride and 6-diazo-5-oxo-L-norleucine blocked HBP-mediated O-GlcNAcylation and suppressed tumor progression in liver-specific Pck1-knockout mice. We reveal a link between PCK1 depletion and hyper-O-GlcNAcylation that underlies HCC oncogenesis and suggest therapeutic targets for HCC that act by inhibiting O-GlcNAcylation., Introduction Gaining insight into the fundamental role of metabolic reprogramming in cancer has contributed immensely to our understanding of tumorigenesis and cancer progression (1). Nutrient limitations (such as glucose deprivation) [...]
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- 2021
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22. Endoplasmic reticulum stress sensor IRE1[alpha] propels neutrophil hyperactivity in lupus
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Sule, Gautam, Abuaita, Basel H., Steffes, Paul A., Fernandes, Andrew T., Estes, Shanea K., Dobry, Craig, Pandian, Deepika, Gudjonsson, Johann E., Kahlenberg, J. Michelle, O'Riordan, Mary X., and Knight, Jason S.
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Enzymes -- Regulation ,Lupus -- Genetic aspects -- Development and progression -- Care and treatment ,Immune response -- Genetic aspects ,Health care industry - Abstract
Neutrophils amplify inflammation in lupus through the release of neutrophil extracellular traps (NETs). The endoplasmic reticulum stress sensor inositol-requiring enzyme1[alpha] (IRE1[alpha]) has been implicated as a perpetuator of inflammation in various chronic diseases; however, IRE1[alpha] has been little studied in relation to neutrophil function or lupus pathogenesis. Here, we found that neutrophils activated by lupus-derived immune complexes demonstrated markedly increased IRE1[alpha] ribonuclease activity. Importantly, in neutrophils isolated from patients with lupus, we also detected heightened IRE1[alpha] activity that was correlated with global disease activity. Immune complex-stimulated neutrophils produced both mitochondrial ROS (mitoROS) and the activated form of caspase-2 in an IRE1[alpha]-dependent fashion, whereas inhibition of IRE1[alpha] mitigated immune complex-mediated NETosis (in both human neutrophils and a mouse model of lupus). Administration of an IRE1[alpha] inhibitor to lupus- prone MRL/pr mice over 8 weeks reduced mitoROS levels in peripheral blood neutrophils, while also restraining plasma cell expansion and autoantibody formation. In summary, these data identify a role for IRE1[alpha] in the hyperactivity of lupus neutrophils and show that this pathway is upstream of mitochondrial dysfunction, mitoROS formation, and NETosis. We believe that inhibition of the IRE1[alpha] pathway is a novel strategy for neutralizing NETosis in lupus, and potentially other inflammatory conditions., Introduction Systemic lupus erythematosus (SLE), which is commonly referred to as lupus, is a prototypical systemic autoimmune disease. The immunopathology of lupus is complex, with derangements present in both lymphoid- [...]
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- 2021
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23. Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease
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Sidhom, Eriene-Heidi, Kim, Choah, Kost-Alimova, Maria, Ting, May Theng, Keller, Keith, Avila-Pacheco, Julian, Watts, Andrew J.B., Vernon, Katherine A., Marshall, Jamie L., Reyes-Bricio, Estefania, Racette, Matthew, Wieder, Nicolas, Kleiner, Giulio, Grinkevich, Elizabeth J., Chen, Fei, Weins, Astrid, Clish, Clary B., Shaw, Jillian L., Quinzii, Catarina M., and Greka, Anna
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Enzymes -- Regulation ,Ubiquinones -- Health aspects ,Cellular signal transduction -- Genetic aspects -- Health aspects ,Kidney diseases -- Genetic aspects -- Development and progression -- Care and treatment ,Health care industry - Abstract
Mutations affecting mitochondrial coenzyme Q (CoQ) biosynthesis lead to kidney failure due to selective loss of podocytes, essential cells of the kidney filter. Curiously, neighboring tubular epithelial cells are spared early in disease despite higher mitochondrial content. We sought to illuminate noncanonical, cell-specific roles for CoQ, independently of the electron transport chain (ETC). Here, we demonstrate that CoQ depletion caused by Pdss2 enzyme deficiency in podocytes results in perturbations in polyunsaturated fatty acid (PUFA) metabolism and the Braf/Mapk pathway rather than ETC dysfunction. Single-nucleus RNA-Seq from kidneys of [Pdss2.sup.kd/kd] mice with nephrotic syndrome and global CoQ deficiency identified a podocyte-specific perturbation of the Braf/Mapk pathway. Treatment with GDC-0879, a Braf/Mapk-targeting compound, ameliorated kidney disease in [Pdss2.sup.kd/kd] mice. Mechanistic studies in Pdss2-depleted podocytes revealed a previously unknown perturbation in PUFA metabolism that was confirmed in vivo. Gpx4, an enzyme that protects against PUFA- mediated lipid peroxidation, was elevated in disease and restored after GDC-0879 treatment. We demonstrate broader human disease relevance by uncovering patterns of GPX4 and Braf/Mapk pathway gene expression in tissue from patients with kidney diseases. Our studies reveal ETC-independent roles for CoQ in podocytes and point to Braf/Mapk as a candidate pathway for the treatment of kidney diseases., Introduction Deep mechanistic understanding of genetically defined diseases can provide insight into fundamental biology and potential therapeutic targets for the treatment of rare and prevalent diseases (1-7). Mitochondrial cytopathies are [...]
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- 2021
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24. Oxidized CaMKII and 0-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms
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Mesubi, Olurotimi O., Rokita, Adam G., Abrol, Neha, Wu, Yuejin, Chen, Biyi, Wang, Qinchuan, Granger, Jonathan M., Tucker- Bartley, Anthony, Luczak, Elizabeth D., Murphy, Kevin R., Umapathi, Priya, Banerjee, Partha S., Boronina, Tatiana N., Cole, Robert N., Maier, Lars S., Wehrens, Xander H., Pomerantz, Joel L., Song, Long-Sheng, Ahima, Rexford S., Hart, Gerald W., Zachara, Natasha E., and Anderson, Mark E.
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Enzymes -- Regulation ,Diabetes -- Complications and side effects -- Care and treatment -- Genetic aspects ,Atrial fibrillation -- Development and progression -- Care and treatment -- Genetic aspects ,Phosphotransferases -- Health aspects ,Molecular targeted therapy -- Innovations ,Health care industry - Abstract
Diabetes mellitus (DM) and atrial fibrillation (AF) are major unsolved public health problems, and diabetes is an independent risk factor for AF. However, the mechanism(s) underlying this clinical association is unknown. ROS and protein OGlcNAcylation (OGN) are increased in diabetic hearts, and calmodulin kinase II (CaMKII) is a proarrhythmic signal that may be activated by ROS (oxidized CaMKII, ox-CaMKII) and OGN (OGN-CaMKII). We induced type 1 (T1D) and type 2 DM (T2D) in a portfolio of genetic mouse models capable of dissecting the role of ROS and OGN at CaMKII and global OGN in diabetic AF. Here, we showed that T1D and T2D significantly increased AF, and this increase required CaMKII and OGN. T1D and T2D both required ox-CaMKII to increase AF; however, we did not detect OGN-CaMKII or a role for OGN-CaMKII in diabetic AF. Collectively, our data affirm CaMKII as a critical proarrhythmic signal in diabetic AF and suggest ROS primarily promotes AF by ox-CaMKII, while OGN promotes AF by a CaMKII-independent mechanism(s). These results provide insights into the mechanisms for increased AF in DM and suggest potential benefits for future CaMKII and OGN targeted therapies., Introduction Atrial fibrillation (AF) and diabetes mellitus (DM) are major, unsolved public health problems (1-3). The burden of both conditions is projected to increase significantly in the United States and [...]
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- 2021
25. Doubling up on function: dual-specificity tyrosine-regulated kinase 1A (DYRK1A) in B cell acute lymphoblastic leukemia
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Kim, Jung-Hyun, Li, Liping, and Resar, Linda M.S.
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Enzymes -- Regulation ,Phosphotransferases -- Health aspects ,Acute lymphocytic leukemia -- Genetic aspects -- Development and progression -- Care and treatment ,Health care industry - Abstract
DYRK1A, the dual-specificity kinase, is again doubling up on function, as reported by Bhansali, Rammohan, and colleagues in this issue of the JCI. DYRK1A is an evolutionarily conserved protein kinase with dual specificity; it adds phosphates to serine/threonine residues of diverse regulatory proteins and activates its own function by autophosphorylating a critical tyrosine at position 321 in the activation loop. Bhansali, Rammohan, and colleagues investigated B cell acute lymphoblastic leukemia (B-ALL) in individuals with Down syndrome (DS) and in children with leukemia characterized by aneuploidy. The study revealed a DYRK1A/FOXO1 and STAT3 signaling pathway in B-ALL that could be targeted pharmacologically, thus opening the door to therapeutic strategies for patients with leukemia with or without DS., DYRK1A protein kinases Kinases comprise a large class of eukaryotic proteins that evolved to regulate key cellular processes by chemically adding phosphates to modulate protein function. DYRK1A (dual-specificity tyrosine-regulated kinase [...]
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- 2021
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26. Protein tyrosine phosphatase nonreceptor type 2 controls colorectal cancer development
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Katkeviciute, Egle, Hering, Larissa, Montalban-Arques, Ana, Busenhart, Philipp, Schwarzfischer, Marlene, Manzini, Roberto, Conde, Javier, Atrott, Kirstin, Lang, Silvia, Rogler, Gerhard, Naschberger, Elisabeth, Schellerer, Vera S., Sturzl, Michael, Rickenbacher, Andreas, Turina, Matthias, Weber, Achim, Leibl, Sebastian, Leventhal, Gabriel E., Levesque, Mitchell, Boyman, Onur, Scharl, Michael, and Spalinger, Marianne R.
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Enzymes -- Regulation ,Colorectal cancer -- Genetic aspects -- Development and progression -- Care and treatment ,Esterases -- Health aspects ,Immunotherapy -- Methods -- Patient outcomes ,Health care industry - Abstract
Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) recently emerged as a promising cancer immunotherapy target. We set out to investigate the functional role of PTPN2 in the pathogenesis of human colorectal carcinoma (CRC), as its role in immune-silent solid tumors is poorly understood. We demonstrate that in human CRC, increased PTPN2 expression and activity correlated with disease progression and decreased immune responses in tumor tissues. In particular, stage II and III tumors displayed enhanced PTPN2 protein expression in tumor-infiltrating T cells, and increased PTPN2 levels negatively correlated with expression of PD-1, CTLA4, STAT1, and granzyme A. In vivo, T cell- and DC-specific PTPN2 deletion reduced tumor burden in several CRC models by promoting [CD44.sup.+] effector/memory T cells, as well as [CD8.sup.+] T cell infiltration and cytotoxicity in the tumor. In direct relevance to CRC treatment, T cell-specific PTPN2 deletion potentiated anti-PD-1 efficacy and induced antitumor memory formation upon tumor rechallenge in vivo. Our data suggest a role for PTPN2 in suppressing antitumor immunity and promoting tumor development in patients with CRC. Our in vivo results identify PTPN2 as a key player in controlling the immunogenicity of CRC, with the strong potential to be exploited for cancer immunotherapy., Introduction Colorectal carcinoma (CRC) is the third most frequent malignancy and the second leading cause of cancer-related deaths worldwide (1, 2). In 2018, more than 1.8 million patients were newly [...]
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- 2021
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27. Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis
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Mole, Damian J., Webster, Scott P., Uings, Iain, Zheng, Xiaozhong, Binnie, Margaret, Wilson, Kris, Hutchinson, Jonathan P., Mirguet, Olivier, Walker, Ann, Beaufils, Benjamin, Ancellin, Nicolas, Trottet, Lionel, Beneton, Veronique, Mowat, Christopher G., Wilkinson, Martin, Rowland, Paul, Haslam, Carl, McBride, Andrew, Homer, Natalie Z.M., Baily, James E., Sharp, Matthew G.F., Garden, O. James, Hughes, Jeremy, Howie, Sarah E.M., Holmes, Duncan S., Liddle, John, and Iredale, John P.
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Multiple organ failure -- Genetic aspects -- Prevention ,Enzymes -- Regulation ,Pancreatitis -- Genetic aspects -- Development and progression ,Oxidases -- Health aspects ,Biological sciences ,Health - Abstract
Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death (1,2). Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population (4). There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism (5), is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 A resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness., Systemic tryptophan metabolism in mammals occurs primarily via the kynurenine pathway (Fig. 1a) (5). Tryptophan metabolites contribute to acute lung injury in rats with [AP.sup.6], and the tryptophan metabolite kynurenine [...]
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- 2016
28. DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys
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Chang, Yu-Ting, Yang, Ching-Chin, Pan, Szu-Yu, Chou, Yu-Hsiang, Chang, Fan-Chi, Lai, Chun-Fu, Tsai, Ming-Hsuan, Hsu, Huan-Lun, Lin, Ching-Hung, Chiang, Wen-Chih, Wu, Ming-Shiou, Chu, Tzong-Shinn, Chen, Yung-Ming, and Lin, Shuei-Liong
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Fibrosis -- Genetic aspects -- Development and progression ,Enzymes -- Regulation ,Erythropoietin -- Health aspects ,Kidney diseases -- Genetic aspects -- Development and progression ,Health care industry - Abstract
Renal erythropoietin-producing cells (REPCs) remain in the kidneys of patients with chronic kidney disease, but these cells do not produce sufficient erythropoietin in response to hypoxic stimuli. Treatment with HIF stabilizers rescues erythropoietin production in these cells, but the mechanisms underlying the decreased response of REPCs in fibrotic kidneys to anemic stimulation remain elusive. Here, we show that fibroblast-like [FOXD1.sup.+] progenitor-derived kidney pericytes, which are characterized by the expression of α1 type I collagen and PDGFRβ, produce erythropoietin through HIF2α regulation but that production is repressed when these cells differentiate into myofibroblasts. DNA methyltransferases and erythropoietin hypermethylation are upregulated in myofibroblasts. Exposure of myofibroblasts to nanomolar concentrations of the demethylating agent 5-azacytidine increased basal expression and hypoxic induction of erythropoietin. Mechanistically, the profibrotic factor TGF-β1 induced hypermethylation and repression of erythropoietin in pericytes; these effects were prevented by 5-azacytidine treatment. These findings shed light on the molecular mechanisms underlying erythropoietin repression in kidney myofibroblasts and demonstrate that clinically relevant, nontoxic doses of 5-azacytidine can restore erythropoietin production and ameliorate anemia in the setting of kidney fibrosis in mice., Introduction Low levels of plasma erythropoietin (EPO) that are disproportional to the degree of anemia are often observed in patients with chronic kidney disease (CKD) (1, 2). However, the oxygen-EPO-hemoglobin [...]
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- 2016
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29. Time Evolution of the Millisecond Allosteric Activation of Imidazole Glycerol Phosphate Synthase
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Carla Calvó-Tusell, Miguel A. Maria-Solano, Sílvia Osuna, Ferran Feixas, Agencia Estatal de Investigación, and European Commission
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Anions ,Binding Sites ,Glutamine ,Monomers ,Glicerina ,Glycerin ,Enzims -- Regulació ,General Chemistry ,Biochemistry ,Catalysis ,Monòmers ,Colloid and Surface Chemistry ,Allosteric Regulation ,Aminohydrolases ,Enzymes -- Regulation ,Glicerina -- Conformació ,Glycerin -- Conformation - Abstract
Deciphering the molecular mechanisms of enzymatic allosteric regulation requires the structural characterization of functional states and also their time evolution toward the formation of the allosterically activated ternary complex. The transient nature and usually slow millisecond time scale interconversion between these functional states hamper their experimental and computational characterization. Here, we combine extensive molecular dynamics simulations, enhanced sampling techniques, and dynamical networks to describe the allosteric activation of imidazole glycerol phosphate synthase (IGPS) from the substrate-free form to the active ternary complex. IGPS is a heterodimeric bienzyme complex whose HisH subunit is responsible for hydrolyzing glutamine and delivering ammonia for the cyclase activity in HisF. Despite significant advances in understanding the underlying allosteric mechanism, essential molecular details of the long-range millisecond allosteric activation of IGPS remain hidden. Without using a priori information of the active state, our simulations uncover how IGPS, with the allosteric effector bound in HisF, spontaneously captures glutamine in a catalytically inactive HisH conformation, subsequently attains a closed HisF:HisH interface, and finally forms the oxyanion hole in HisH for efficient glutamine hydrolysis. We show that the combined effector and substrate binding dramatically decreases the conformational barrier associated with oxyanion hole formation, in line with the experimentally observed 4500-fold activity increase in glutamine hydrolysis. The allosteric activation is controlled by correlated time-evolving dynamic networks connecting the effector and substrate binding sites. This computational strategy tailored to describe millisecond events can be used to rationalize the effect of mutations on the allosteric regulation and guide IGPS engineering efforts The authors thank the Generalitat de Catalunya for the emerging group CompBioLab (2017 SGR-1707) and Spanish MINECO for projects PGC2018-102192-B-I00 (S.O), RTI2018-101032-J100 (F.F), and RYC2020-029552-I (F.F.). S.O. is grateful for the funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Program (ERC-2015-StG-679001) and the Human Frontier Science Program (HFSP) for Project Grant RGP0054/2020. F.F. thanks the Spanish Supercomputing Network (RES) for access to supercomputing resources (Project BCV-2021-1-0015). M.A.M.-S. was supported by the National Research Foundation of Korea (NRF) under the Brain Pool Program (NRF2021H1D3A2A02038434). Open Access funding provided thanks to the CRUE-CSIC agreement with ACS.
- Published
- 2022
30. Oxidative stress and damage to erythrocytes in patients with chronic obstructive pulmonary disease--changes in ATPase and acetylcholinesterase activity
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Bukowska, Bozena, Sicinska, Paulina, Pajak, Aneta, Koceva-Chyla, Aneta, Pietras, Tadeusz, Pszczolkowska, Anna, Gorski, Pawel, and Koter-Michalak, Maria
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Enzymes -- Regulation ,Lung diseases, Obstructive -- Genetic aspects -- Development and progression ,Erythrocytes -- Genetic aspects ,Oxidative stress -- Health aspects ,Biological sciences - Abstract
Abstract: The study indicates, for the first time, the changes in both ATPase and AChE activities in the membrane of red blood cells of patients diagnosed with COPD. Chronic obstructive [...]
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- 2015
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31. Histone deacetylase 6 inhibition enhances oncolytic viral replication in glioma
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Nakashima, Hiroshi, Kaufmann, Johanna K., Wang, Pin-Yi, Nguyen, Tran, Speranza, Maria-Carmela, Kasai, Kazue, Okemoto, Kazuo, Otsuki, Akihiro, Nakano, Ichiro, Fernandez, Soledad, Goins, William F., Grandi, Paola, Glorioso, Joseph C., Lawler, Sean, Cripe, Timothy P., and Chiocca, E. Antonio
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Enzymes -- Regulation ,Gliomas -- Analysis -- Health aspects -- Care and treatment ,Biological products -- Health aspects ,Health care industry - Abstract
Oncolytic viral (OV) therapy, which uses genetically engineered tumor-targeting viruses, is being increasingly used in cancer clinical trials due to the direct cytolytic effects of this treatment that appear to provoke a robust immune response against the tumor. As OVs enter tumor cells, intrinsic host defenses have the potential to hinder viral replication and spread within the tumor mass. In this report, we show that histone deacetylase 6 (HDAC6) in tumor cells appears to alter the trafficking of postentry OVs from the nucleus toward lysosomes. In glioma cell lines and glioma-stem-like cells, HDAC6 inhibition (HDAC6i) by either pharmacologic or genetic means substantially increased replication of oncolytic herpes simplex virus type 1 (oHSV). Moreover, HDAC6i increased shuttling of post-entry oHSV to the nucleus. In addition, electron microscopic analysis revealed that post-entry oHSVs are preferentially taken up into glioma cells through the endosomal pathway rather than via fusion at the cell surface. Together, these findings illustrate a mechanism of glioma cell defense against an incoming infection by oHSV and identify possible approaches to enhance oHSV replication and subsequent lysis of tumor cells., Introduction Malignant gliomas (such as glioblastoma [GBM]) remain formidable cancers based on their poor prognosis, with a median survivorship of 15 months or less, extensive neurologic morbidity, and cost of [...]
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- 2015
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32. Mediator kinase inhibition further activates super-enhancer-associated genes in AML
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Pelish, Henry E., Liau, Brian B., Nitulescu, Ioana I., Tangpeerachaikul, Anupong, Poss, Zachary C., Silva, Diogo H. Da, Caruso, Brittany T., Arefolov, Alexander, Fadeyi, Olugbeminiyi, Christie, Amanda L., Du, Karrie, Banka, Deepti, Schneider, Elisabeth V., Jestel, Anja, Zou, Ge, Si, Chong, Ebmeier, Christopher C., Bronson, Roderick T., Krivtsov, Andrei V., Myers, Andrew G., Kohl, Nancy E., Kung, Andrew L., Armstrong, Scott A., Lemieux, Madeleine E., Taatjes, Dylan J., and Shair, Matthew D.
- Subjects
Enzymes -- Regulation ,Phosphotransferases -- Properties ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity [...]
- Published
- 2015
33. Acute inhibition of monoamine oxidase and ischemic preconditioning in isolated rat hearts: interference with postischemic functional recovery but no effect on infarct size reduction
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Danila, Maria D., Privistirescu, Andreea I., Mirica, Silvia N., Sturza, Adrian, Ordodi, Valentin, Noveanu, Lavinia, Duicu, Oana M., and Muntean, Danina M.
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Heart diseases -- Development and progression -- Care and treatment ,Enzymes -- Regulation ,Monoamine oxidase -- Health aspects ,Biological sciences - Abstract
Monoamine oxidases (MAOs) have recently emerged as important mitochondrial sources of oxidative stress in the cardiovascular system. Generation of reactive oxygen species during the brief episodes of ischemic preconditioning (IPC) is responsible for the cardioprotection at reperfusion. The aim of this study was to assess the effects of two MAO inhibitors (clorgyline and pargyline) on the IPC-related protection in isolated rat hearts. Animals subjected to 30 min global ischemia and 120 min reperfusion were assigned to the following groups: (i) Control, no additional intervention; (ii) IPC, 3 cycles of 5 min ischemia and 5 min reperfusion before the index ischemia; (iii) IPC-clorgyline, IPC protocol bracketed for 5 min with clorgyline (50 µmol/L); (iv) IPC-pargyline, IPC protocol bracketed for 5 min with pargyline (0.5 mmol/L). The postischemic functional recovery was assessed by the left ventricular developed pressure (LVDP) and the indices of contractility (+dLVP/dt max) and relaxation (-dLVP/dt max). Infarct size (IS) was quantified by TTC staining. In both genders, IPC significantly improved functional recovery that was further enhanced in the presence of either clorgyline or pargyline. IS reduction was comparable among all the preconditioned groups, regardless of the presence of MAO inhibitors. In isolated rat hearts, acute inhibition of MAOs potentiates the IPC-induced postischemic functional recovery without interfering with the anti-necrotic protection. Key words: monoamine oxidase, MAO inhibitors, ischemic preconditioning, isolated rat heart. Les monoamine oxydases (MAOs) se sont recemment revelees d'importantes sources de stress oxydatif mitochondrial dans le systeme cardiovasculaire. La generation de derives reactifs de l'oxygene au cours d'episodes brefs de preconditionnement ischemique (PCI) est responsable de la cardioprotection lors de la reperfusion. La presente etude visait a evaluer les effets de deux inhibiteurs de la MAO (la clorgyline et la pargyline) sur le PCI dans un modele de caeur isole de rat. Nous avons soumis les animaux a une ischemie globale de 30 min, puis a une reperfusion de 120 min et les avons repartis dans les groupes suivants: (i) temoin (aucune intervention supplementaire), (ii) PCI (3 cycles de 5 min d'ischemie suivis de 5 min de reperfusion avant l'ischemie de reference), (iii) PCI-clorgyline (protocole de PCI alternant avec l'administration de clorgyline a 50 µmol/L pendant 5 min) et (iv) PCI-pargyline (protocole de PCI alternant avec l'administration de pargyline a 0,5 mmol/L pendant 5 min). Nous avons ensuite evalue le retablissement fonctionnel post-ischemique en mesurant la pression ventriculaire gauche developpee (PVGD) ainsi que les indices de contractilite (+dP/dt max) et de relaxation (-dP/dt max). Enfin, nous avons quantifie la taille de l'infarctus par la technique de coloration au TTC. Chez les animaux des deux sexes, le PCI a permis d'ameliorer clairement le retablissement fonctionnel qui a ete accentue en presence de clorgyline ou de pargyline. Par ailleurs, la diminution de la taille de l'infarctus etait comparable dans tous les groupes soumis au preconditionnement, et ce, sans egard a la presence d'inhibiteurs de la MAO. En somme, dans les caeurs isoles de rat, l'administration a court terme d'inhibiteurs de la MAO potentialise la recuperation fonctionnelle post-ischemique induite par le PCI, sans nuire a la protection contre la necrose. [Traduit par la Redaction] Mots-cles: monoamine-oxydase, inhibiteurs de la MAO, preconditionnement ischemique, caeur isole de rat., Introduction Coronary heart disease remains the leading cause of mortality and morbidity due to heart failure worldwide (Go et al. 2014). In the past decades, mitochondria have emerged as key [...]
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- 2015
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34. Endotoxin exposure and puberty in female rats: the role of nitric oxide and caspase-1 inhibition in neonates
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Ozgocer, Tuba, Yildiz, Sedat, Elbe, Hulya, and Vardi, Nigar
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Enzymes -- Regulation ,Endotoxins -- Health aspects ,Lipopolysaccharides -- Properties ,Molecular targeted therapy -- Innovations ,Physics - Abstract
Bacterial toxins are widespread in the environment as well as in the digestive system of humans and animals. Toxin from Gram-negative bacteria (endotoxin or lipopolysaccharide; LPS) has a life-long programming effect on reproduction in rats, but the mediators have not been well-documented, so we investigated the effects of LPS on the timing of puberty in female rats. Because the levels of nitric oxide (NO) and interleukin 1β (IL-10) increase following injection of LPS, we injected neonates (post-natal day (pnd) 7) with LPS, with or without NO or IL-1β inhibitors. Half of the prepubescent (pnd 30) animals received an additional LPS injection. Vaginal opening, number of ovarian follicles, and serum anti-LPS antibodies were determined. A single LPS injection was sufficient to reduce the primordial follicle pool, but puberty was delayed when rats received 2 LPS injections (at pnd 7 and 30). NO or IL-1β inhibitors improved both of these parameters, suggesting that the early detrimental effects of LPS on puberty and primordial follicle pool are mediated by NO and IL-1β. Key words: lipopolysaccharide, puberty, ovarian function, IL-1β, nitric oxide, female rats. Les toxines bacteriennes sont repandues dans l'environnement et dans le systeme digestif des humains et des animaux. On sait que la toxine des bacteries negatives a Gram (endotoxine ou lipopolysaccharide; LPS) exerce un effet de programmation sur la reproduction des rats qui dure toute la vie, mais ses mediateurs ne sont pas bien documentes. Puisque les niveaux d'oxyde nitrique (NO) et d'interleukine 1β (IL-10) augmentent a la suite d'une injection de LPS, les auteurs ont examine les effets d'une injection neonatale de LPS (jour 7 postnatal) en presence ou non d'inhibiteurs de NO ou d'IL-1β, sur la maturation pubertaire de rats femelles. La moitie des animaux a recu une injection supplementaire de LPS en periode pre-pubertaire (jour 30 postnatal). L'ouverture vaginale, le nombre de follicules ovariens et la presence d'anticorps anti-LPS dans le serum ont ete determines. Une injection unique de LPS suffisait a reduire le pool de follicules primordiaux mais la puberte n'etait retardee que chez les rates ayant recu deux injections de LPS, aux jours 7 et 30 postnataux. Les inhibiteurs amelioraient les deux parametres, suggerant que les effets nocifs precoces du LPS sur la puberte et le pool de follicules primordiaux passent par l'intermediaire du NO et de l'IL-1β. [Traduit par la Redaction] Mots-cles: lipopolysaccharide, puberte, fonction ovarienne, IL-1β, oxyde nitrique, rats femelles., Introduction The environmental chemicals that have an impact on human health are not only man-made or man-introduced agents (Rylander 2002); humans are continuously exposed to toxins originating from microorganism-associated molecular [...]
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- 2015
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35. Telmisartan reduces atrial arrhythmia susceptibility through the regulation of RAS-ERK and PI3K-Akt-eNOS pathways in spontaneously hypertensive rats
- Author
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Wang, Wei-wei, Zhang, Fei-long, Chen, Jian-hua, Chen, Xue-hai, Fu, Fa-yuan, Tang, Mi-rong, and Chen, Liang-long
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Enzymes -- Regulation ,Arrhythmia -- Prevention ,Telmisartan -- Patient outcomes ,Physics - Abstract
Telmisartan is an angiotensin II receptor blocker that displays unique PPAR-γ modulating activity. PPAR-γ agonists have been shown to decrease susceptibility to atrial fibrillation through their antioxidant and antiapoptotic effects. The aim of this study was to determine whether telmisartan would have a greater effect on susceptibility to atrial arrhythmia in a hypertensive rat model than valsartan, which is a traditional angiotensin II receptor blocker. In this study, spontaneously hypertensive rats were treated with 10 mg x [(kg body mass).sup.-1] x [d.sup.-1] telmisartan (TEL group), 10 mg x [(kg body mass).sup.-1] x [d.sup.-1] valsartan (VAL group), or vehicle (saline; SHR group) for 4 weeks. Age-matched Wistar-Kyoto rats (WKY) were used as normotensive controls. After 4 weeks of treatment, we performed echocardiographic assessment, electrophysiological analysis, histological evaluation, and Western blot analysis. Telmisartan decreased systolic blood pressure to a similar extent as valsartan. Relative to the WKY controls, atrial arrhythmia susceptibility was significantly increased in the SHR group, and was significantly decreased by both telmisartan and valsartan, albeit to a greater extent with telmisartan. Arrhythmogenic atrial remodeling, including enlargement of the left atrium, myocyte hypertrophy, interstitial fibrosis, and myocyte apoptosis, was observed in the SHR group, and was accompanied by activated RAS-ERK signaling and suppressed PI3K-Akt-eNOS signaling. The results suggest that telmisartan reduced susceptibility to atrial arrhythmia to a greater extent than valsartan, ameliorated atrial remodeling, and reversed imbalances in the RAS-ERK and PI3K-Akt-eNOS pathways. Key words: hypertension, atrial fibrillation, structural remodeling, angiotensin receptor blockers, signaling pathway. Le telmisartan est un antagoniste du recepteur de l'angiotensine II qui exerce une activite modulatrice PPAR-γ unique. Les agonistes du PPAR-γ se sont averes diminuer la susceptibilite a la fibrillation auriculaire grace a leurs proprietes antioxydantes et anti-apoptose. Le but de cette etude etait de determiner si le telmisartan exercerait un effet sur la susceptibilite a l'arythmie auriculaire superieur a celui du valsartan, un antagoniste du recepteur de l'angiotensine II traditionnel, dans un modele de rats hypertendus. Dans cette etude, des rats spontanement hypertendus (SHR) ont ete traites avec 10 mg x [(kg de masse corporelle).sup.-1] x [jour.sup.-1] de telmisartan (TEL), 10 mg-(kg de masse corporelle)-1-jour-1 de valsartan (VAL) ou le vehicule (saline) pendant 4 semaines. Des rats Wistar-Kyoto (WKY) appareilles suivant l'age ont ete utilises comme controles normotensifs. Apres 4 semaines de traitement, des evaluations par echocardiographie, des analyses par electrophysiologie, des evaluations histologiques et des buvardages Western ont ete realises. Le telmisartan diminuait la pression sanguine systolique au meme degre que le valsartan. Comparativement aux controles WKY, la susceptibilite a l'arythmie auriculaire etait significativement accrue chez les rats SHR et significativement diminuee par le telmisartan et la valsartan, quoique le telmisartan ait ete plus efficace (TEL vs VAL). Un remodelage auriculaire arythmogenique, incluant l'elargissement de l'oreillette gauche, l'hypertrophie des myocytes, la fibrose interstitielle et l'apoptose des myocytes, etait observe chez les animaux SHR et il etait accompagne d'une activation de la signalisation RAS-ERK et d'une suppression de la signalisation PI3K-Akt-eNOS. Ces resultats suggerent que le telmisartan a reduit la susceptibilite a l'arythmie auriculaire dans une plus large mesure que le valsartan, a ameliore le remodelage auriculaire et a renverse les debalancements entre les voies de signalisation RAS-ERK et PI3K-Akt-eNOS. [Traduit par la Redaction] Mots-cles : hypertension, fibrillation auriculaire, remodelage structural, antagonistes du recepteur de l'angiotensine, voie de signalisation., Introduction Atrial fibrillation (AF), an important risk factor for stroke and mortality, is the most prevalent arrhythmia diagnosed in clinical practice (Wilhelmsen et al. 2001). Hypertension is a strong and [...]
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- 2015
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36. Structure of the key species in the enzymatic oxidation of methane to methanol
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Banerjee, Rahul, Proshlyakov, Yegor, Lipscomb, John D., and Proshlyakov, Denis A.
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Methane -- Properties ,Enzymes -- Regulation ,Biosynthesis -- Genetic aspects ,Chemical research ,Oxidation-reduction reaction -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Methane monooxygenase (MMO) catalyses the [O.sub.2]-dependent conversion of methane to methanol in methanotrophic bacteria, thereby preventing the atmospheric egress of approximately one billion tons of this potent greenhouse gas annually. The key reaction cycle intermediate of the soluble form of MMO (sMMO) is termed compound Q (Q). Q contains a unique dinuclear [Fe.sup.IV] cluster that reacts with methane to break an exceptionally strong 105 kcal [mol.sup.-1] C-H bond and insert one oxygen atom (1,2). No other biological oxidant, except that found in the particulate form of MMO, is capable of such catalysis. The structure of Q remains controversial despite numerous spectroscopic, computational and synthetic model studies (2-7). A definitive structural assignment can be made from resonance Raman vibrational spectroscopy but, despite efforts over the past two decades, no vibrational spectrum of Q has yet been obtained. Here we report the core structures of Q and the following product complex, compound T, using time-resolved resonance Raman spectroscopy (TR3). TR3 permits fingerprinting of intermediates by their unique vibrational signatures through extended signal averaging for shortlived species. We report unambiguous evidence that Q possesses a bis-p-oxo diamond core structure and show that both bridging oxygens originate from [O.sub.2]. This observation strongly supports a homolytic mechanism for O-O bond cleavage. We also show that T retains a single oxygen atom from [O.sub.2] as a bridging ligand, while the other oxygen atom is incorporated into the product (8). Capture of the extreme oxidizing potential of Q is of great contemporary interest for bioremediation and the development of synthetic approaches to methane-based alternative fuels and chemical industry feedstocks. Insight into the formation and reactivity of Q from the structure reported here is an important step towards harnessing this potential., Transient kinetic studies of sMMO have revealed eight reaction cycle intermediates, thereby providing the most comprehensive description of enzymatic [O.sub.2] activation and C-H bond oxidation currently available for any di-iron [...]
- Published
- 2015
37. Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation
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Erickson, Jeffrey R., Pereira, Laetitia, Wang, Lianguo, Han, Guanghui, Ferguson, Amanda, Dao, Khanha, Copeland, Ronald J., Despa, Florin, Hart, Gerald W., Ripplinger, Crystal M., and Bers, Donald M.
- Subjects
Medical research ,Medicine, Experimental ,Enzymes -- Regulation ,Glycosylation -- Physiological aspects ,Protein biosynthesis -- Research ,Arrhythmia -- Risk factors ,Protein kinases -- Physiological aspects ,Hyperglycemia -- Complications and side effects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
[Ca.sup.2+]/calmodulin-dependent protein kinase II (CaMKII) is an enzyme with important regulatory functions in the heart and brain, and its chronic activation can be pathological. CaMKII activation is seen in heart failure, and can directly induce pathological changes in ion channels, [Ca.sup.2+] handling and gene transcription (1). Here, in human, rat and mouse, we identify a novel mechanism linking CaMKII and hyperglycaemic signalling in diabetes mellitus, which is a key risk factor for heart (2) and neurodegenerative diseases (3,4). Acute hyperglycaemia causes covalent modification of CaMKII by O-linked Nacetylglucosamine (OGlcNAc). O-GlcNAc modification of CaMKII at Ser279 activates CaMKII autonomously, creating molecular memory even after [Ca.sup.2+] concentration declines. O-GlcNAc-modified CaMKII is increased in the heart and brain of diabetic humans and rats. In cardiomyocytes, increased glucose concentration significantly enhances CaMKII-dependent activation of spontaneous sarcoplasmic reticulum [Ca.sup.2+] release events that can contribute to cardiac mechanical dysfunction and arrhythmias (1). These effects were prevented by pharmacological inhibition of O-GlcNAc signalling or genetic ablation of CaMKII8. In intact perfused hearts, arrhythmias were aggravated by increased glucose concentration through O-GlcNAc- and CaMKII-dependent pathways. In diabetic animals, acute blockade ofO-GlcNAc inhibited arrhythmogenesis. Thus, O-GlcNAc modification of CaMKII is a novel signalling event in pathways that may contribute critically to cardiac and neuronal pathophysiology in diabetes and other diseases., Under basal conditions, CaMKII is autoinhibited by an interaction between the regulatory and catalytic subunits of each CaMKII monomer (Fig. 1a). [Ca.sup.2+]/calmodulin ([Ca.sup.2+]/CaM) binding to the regulatory domain disrupts autoinhibition, [...]
- Published
- 2013
38. Modulation of allostery by protein intrinsic disorder
- Author
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Ferreon, Allan Chris M., Ferreon, Josephine C., Wright, Peter E., and Deniz, Ashok A.
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Enzymes -- Regulation ,Protein-protein interactions -- Research ,Cell interaction -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Allostery is an intrinsic property of many globular proteins and enzymes that is indispensable for cellular regulatory and feedback mechanisms. Recent theoretical (1) and empirical (2) observations indicate that allostery [...]
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- 2013
39. BAF complexes facilitate decatenation of DNA by topoisomerase IIα
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Dykhuizen, Emily C., Hargreaves, Diana C., Miller, Erik L., Cui, Kairong, Korshunov, Andrey, Kool, Marcel, Pfister, Stefan, Cho, Yoon-Jae, Zhao, Keji, and Crabtree, Gerald R.
- Subjects
Chromatin -- Properties ,Enzymes -- Regulation ,Genetic regulation -- Research ,Genetic transcription -- Observations ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Recent exon-sequencing studies of human tumours have revealed that subunits of BAF (mammalian SWI/SNF) complexes are mutated in more than 20% of all human malignancies (1,2), but the mechanisms involved [...]
- Published
- 2013
40. Glycyrrhizic acid and 18β-g1ycyrrhetinic acid recover glucocorticoid resistance via PI3K-induced AP1, CRE and NFAT activation
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Kao, Tzu-Chien, Wu, Chi-Hao, and Yen, Gow-Chin
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Corticosteroids ,Steroids -- Health aspects -- Chemical properties ,Enzymes -- Regulation ,Inflammation -- Care and treatment ,Biological sciences ,Health ,Science and technology - Abstract
ARTICLE INFO Article history: Received 10 July 2012 Received in revised form 31 August 2012 Accepted 27 October 2012 Keywords: Glycyrrhizic acid 18β-Glycyrrhetinic acid Glucocorticoid receptor Phosphoinositide 3-kinase Glucocorticoid resistance [...]
- Published
- 2013
41. Aldose reductase drives hyperacetylation of Egr-1 in hyperglycemia and consequent upregulation of proinflammatory and prothrombotic signals
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Vedantham, Srinivasan, Thiagarajan, Devi, Ananthakrishnan, Radha, Wang, Lingjie, Rosario, Rosa, Zou, Yu Shan, Goldberg, Ira, Yan, Shi Fang, Schmidt, Ann Marie, and Ramasamy, Ravichandran
- Subjects
Aldose reductase -- Physiological aspects ,Enzymes -- Regulation ,Acetylation -- Health aspects ,Hyperglycemia -- Physiological aspects ,Health - Abstract
Sustained increases in glucose flux via the aldose reductase (AR) pathway have been linked to diabetic vascular complications. Previous studies revealed that glucose flux via AR mediates endothelial dysfunction and leads to lesional hemorrhage in diabetic human AR (hAR) expressing mice in an [apoE.sup.-/-] background. Our studies revealed sustained activation of Egr-1 with subsequent induction of its downstream target genes tissue factor (TF) and vascular cell adhesion molecule-1 (VCAM-1) in diabetic [apoE.sup.-/-]hAR mice aortas and in high glucose-treated primary murine aortic endothelial cells expressing hAR. Furthermore, we observed that flux via AR impaired [NAD.sup.+] homeostasis and reduced activity of [NAD.sup.+]-dependent deacetylase Sirt-1 leading to acetylation and prolonged expression of Egr-1 in hyperglycemic conditions. In conclusion, our data demonstrate a novel mechanism by which glucose flux via AR triggers activation, acetylation, and prolonged expression of Egr-1 leading to proinflammatory and prothrombotic responses in diabetic atherosclerosis. Diabetes 2014;63:761-774 | DOI: 10.2337/db13-0032, Posttranslational modification (PTM) of histones via deacetylation, mediated by a family of histone deacetylases, was initially identified as a mechanism to silence gene transcription (1,2). In addition, it is well [...]
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- 2014
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42. Collaboration between the essential Esa1 acetyltransferase and the Rpd3 deacetylase is mediated by H4K12 histone acetylation in Saccharomyces cerevisiae
- Author
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Christie S. Chang and Pillus, Lorraine
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Acetylation -- Analysis ,Genetic regulation -- Research ,Histones -- Chemical properties ,Brewer's yeast -- Genetic aspects ,Enzymes -- Regulation ,Enzymes -- Research ,Biological sciences - Published
- 2009
43. Poly (ADP-ribose) polymerase-1-inhibiting flavonoids attenuate cytokine release in blood from male patients with chronic obstructive pulmonary disease or type 2 diabetes
- Author
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Weseler, Antje R., Geraets, Liesbeth, Moonen, Harald J.J., Manders, Ralph J.F., van Loon, Luc J.C., Pennings, Herman-Jan, Wouters, Emiel F.M., Bast, Aalt, and Hageman, Geja J.
- Subjects
Type 2 diabetes -- Care and treatment ,Bioflavonoids -- Health aspects ,Flavones -- Health aspects ,Flavonoids -- Health aspects ,Inflammation -- Care and treatment ,Enzymes -- Regulation ,Enzymes -- Research ,Food/cooking/nutrition - Abstract
Recently, we identified several flavonoids as inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)1 in vitro and in vivo. PARP-1 is recognized as coactivator of nuclear factor-[kappa]B and plays a role in the pathophysiology of diseases with low-grade systemic inflammation, such as chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D). In this study, we assessed the antiinflammatory effects of flavonoids with varying PARP-l-inhibiting effects in whole blood from male patients with COPD or T2D and healthy men. A total of 10 COPD, 10 T2D patients, and 10 healthy volunteers matched for age and BMI were recruited. Blood from each participant was exposed to 1 [micro]g/L lipopolysaccharide (LPS) over 16 h with or without preincubation with 10 [micro]mol/L of flavone, fisetin, morin, or tricetin. Concentrations of tumor necrosis factor (TNF)-[alpha], interleukin (IL)-6, -8, and -10 were measured in the supernatant. Preincubation with fisetin and tricetin strongly attenuated LPS-induced increases in concentrations of TNF[alpha] in blood from COPD patients [mean ([+ or -] SEM): - 41 [+ or -] 4% (fisetin) and -31 [+ or -] 4% (tricetin); P < 0.001] and IL-6 in blood from T2D patients [-31 [+ or -] 5% (fisetin) and -29 +- 6% (tricetin); P
- Published
- 2009
44. In vitro characterization of the enzyme properties of the phospholipid N-methyltransferase PmtA from Agrobacterium tumefaciens
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Aktas, Meriyem and Narberhaus, Franz
- Subjects
Agrobacterium tumefaciens -- Research ,Microbial enzymes -- Physiological aspects ,Microbial enzymes -- Research ,Phospholipids -- Physiological aspects ,Phospholipids -- Research ,Methyltransferases -- Physiological aspects ,Methyltransferases -- Research ,Enzymes -- Regulation ,Enzymes -- Research ,Biological sciences - Abstract
Agrobacterium tumefaciens requires phosphatidylcholine (PC) in its membranes for plant infection. The phospholipid N-methyltransferase PmtA catalyzes all three transmethylation reactions of phosphatidylethanolamine (PE) to PC via the intermediates monomethylphosphatidylethanolamine (MMPE) and dimethylphosphatidylethanolamine (DMPE). The enzyme uses S-adenosylmethionine (SAM) as the methyl donor, converting it to S-adenosylhomocysteine (SAH). Little is known about the activity of bacterial Pmt enzymes, since PC biosynthesis in prokaryotes is rare. In this article, we present the purification and in vitro characterization of A. tumefaciens PmtA, which is a monomeric protein. It binds to PE, the intermediates MMPE and DMPE, the end product PC, and phosphatidylglycerol (PG) and phosphatidylinositol. Binding of the phospholipid substrates precedes binding of SAM. We used a coupled in vitro assay system to demonstrate the enzymatic activity of PmtA and to show that PmtA is inhibited by the end products PC and SAH and the antibiotic sinefungin. The presence of PG stimulates PmtA activity. Our study provides insights into the catalysis and control of a bacterial phospholipid N-methyltransferase.
- Published
- 2009
45. Inhibition of SNF1-related protein kinase1 activity and regulation of metabolic pathways By trehalose-6-phosphate
- Author
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Zhang, Yuhua, Primavesi, Lucia F., Jhurreea, Deveraj, Andralojc, P. John, Mitchell, Rowan A.C., Powers, Stephen J., Schluepmann, Henriette, Delatte, Thierry, Wingler, Astrid, and Paul, Matthew J.
- Subjects
Phosphates -- Properties ,Gene expression -- Research ,Protein kinases -- Properties ,Trehalose -- Properties ,Enzymes -- Regulation ,Enzymes -- Research ,Biological sciences ,Science and technology - Published
- 2009
46. ENaC proteolytic regulation by channel-activating protease 2
- Author
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Garcia-Caballero, Agustin, Dang, Yan, He, Hong, and Stutts, M. Jackson
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Proteases -- Properties ,Sodium channels -- Properties ,Sodium channels -- Physiological aspects ,Proteolysis -- Research ,Enzymes -- Regulation ,Enzymes -- Research ,Biological sciences ,Health - Abstract
Epithelial sodium channels (ENaCs) perform diverse physiological roles by mediating [Na.sup.+] absorption across epithelial surfaces throughout the body. Excessive [Na.sup.+] absorption in kidney and colon elevates blood pressure and in the airways disrupts mucociliary clearance. Potential therapies for disorders of [Na.sup.+] absorption require better understanding of ENaC regulation. Recent work has established partial and selective proteolysis of ENaCs as an important means of channel activation. In particular, channel-activating transmembrane serine proteases (CAPs) and cognate inhibitors may be important in tissue-specific regulation of ENaCs. Although CAP2 (TMPRSS4) requires catalytic activity to activate ENaCs, there is not yet evidence of ENaC fragments produced by this serine protease and/or identification of the site (s) where CAP2 cleaves ENaCs. Here, we report that CAP2 cleaves at multiple sites in all three ENaC subunits, including cleavage at a conserved basic residue located in the vicinity of the degenerin site ([alpha]-K561, [beta]-R503, and [gamma]-R515). Sites in [alpha]-ENaC at K149/R164/K169/R177 and furin-consensus sites in [alpha]-ENaC (R205/R231) and [gamma]-ENaC (R138) are responsible for ENaC fragments observed in oocytes coexpressing CAP2. However, the only one of these demonstrated cleavage events that is relevant for the channel activation by CAP2 takes place in [gamma]-ENaC at position R138, the previously identified furin-consensus cleavage site. Replacement of arginine by alanine or glutamine ([alpha],[beta],[gamma]R138A/Q) completely abolished both the [Na.sup.+] current ([I.sub.Na]) and a 75-kD [gamma]-ENaC fragment at the cell surface stimulated by CAP2. Replacement of [gamma]-ENaC R138 with a conserved basic residue, lysine, preserved both the CAp2-induced [I.sub.Na] and the 75-kD [gamma]-ENaC fragment. These data strongly support a model where CAP2 activates ENaCs by cleaving at R138 in [gamma]-ENaC.
- Published
- 2008
47. Substrate-targeting γ-secretase modulators
- Author
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Kukar, Thomas L., Ladd, Thomas B., Bann, Maralyssa A., Fraering, Patrick C., Narlawar, Rajeshwar, Maharvi, Ghulam M., Healy, Brent, Chapman, Robert, Welzel, Alfred T., Price, Robert W., Moore, Brenda, Rangachari, Vijayaraghavan, Cusack, Bernadette, Eriksen, Jason, Jansen-West, Karen, Verbeeck, Christophe, Yager, Debra, Eckman, Christopher, Ye, Wenjuan, Sagi, Sarah, Cottrell, Barbara A., Torpey, Justin, Rosenberry, Terrone L., Fauq, Abdul, Wolfe, Michael S., Schmidt, Boris, Walsh, Dominic M., Koo, Edward H., and Golde, Todd E.
- Subjects
Enzymes -- Regulation ,Amyloid beta-protein -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation ,Research - Abstract
Selective lowering of Aβ42 levels (the 42-residue isoform of the amyloid-β peptide) with small-molecule γ-secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's [...]
- Published
- 2008
48. Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking
- Author
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Hellmuth, Klaus, Grosskopf, Stefanie, Lum, Ching Tung, Wurtele, Martin, Roder, Nadine, von Kries, Jens Peter, Rosarioo, Marta, Rademann, Jorg, and Birchmeier, Walter
- Subjects
Protein kinases -- Properties ,Phosphatases -- Properties ,Cellular signal transduction -- Evaluation ,Enzymes -- Regulation ,Enzymes -- Evaluation ,Science and technology - Abstract
The protein tyrosine phosphatase Shp2 is a positive regulator of growth factor signaling. Gain-of-function mutations in several types of leukemia define Shp2 as a bona fide oncogene. We performed a high-throughput in silico screen for small-molecular-weight compounds that bind the catalytic site of Shp2. We have identified the phenylhydrazonopyrazolone sulfonate PHPS1 as a potent and cell-permeable inhibitor, which is specific for Shp2 over the closely related tyrosine phosphatases Shpl and PTP1B. PHPS1 inhibits Shp2-dependent cellular events such as hepatocyte growth factor/scatter factor (HGF/SF)-induced epithelial cell scattering and branching morphogenesis. PHPS1 also blocks Shp2-dependent downstream signaling, namely HGF/SF-induced sustained phosphorylation of the Erk1/2 MAP kinases and dephosphorylation of paxillin. Furthermore, PHPS1 efficiently inhibits activation of Erk1/2 by the leukemia-associated Shp2 mutant, Shp2-E76K, and blocks the anchorage-independent growth of a variety of human tumor cell lines. The PHPS compound class is therefore suitable for further development of therapeutics for the treatment of Shp2-dependent diseases. chemical biology | growth factor signaling | phosphatase inhibition | virtual drug screening
- Published
- 2008
49. Anaplastic lymphoma kinase status in lung cancers: An immunohistochemistry and fluorescence in situ hybridization study from a tertiary cancer center in India
- Author
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Murthy, S., Rajappa, S., Gundimeda, S., Mallavarapu, K., Ayyagari, S., Yalavarthi, P., Fonseca, D., Paliwal, P., Nair, Hgr, Koppula, V., Raju, Kvvn, and Rao, S.
- Subjects
Enzymes -- Regulation ,Phosphotransferases -- Health aspects ,Lung cancer -- Genetic aspects -- Diagnosis -- Care and treatment ,Health - Abstract
Byline: S. Murthy, S. Rajappa, S. Gundimeda, K. Mallavarapu, S. Ayyagari, P. Yalavarthi, D. Fonseca, P. Paliwal, HGR. Nair, V. Koppula, KVVN. Raju, S. Rao BACKGROUND AND OBJECTIVES: Fluorescence in [...]
- Published
- 2017
50. Regulation of rice NADPH oxidase by binding of Rac GTPase to its n-terminal extension ([W])([OA])
- Author
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Wong, Hann Ling, Pinontoan, Reinhard, Hayashi, Kokoro, Tabata, Ryo, Yaeno, Takashi, Hasegawa, Kana, Kojima, Chojiro, Yoshioka, Hirofumi, Iba, Koh, Kawasaki, Tsutomu, and Shimamoto, Ko
- Subjects
Plant immunology -- Research ,Oxidases -- Control ,Oxidases -- Properties ,NADP (Coenzyme) -- Properties ,Guanosine triphosphatase -- Properties ,Rice -- Physiological aspects ,Enzymes -- Regulation ,Enzymes -- Research ,Biological sciences ,Science and technology - Published
- 2007
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