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https://www.readbyqxmd.com/read/27905606/a-qm-mm-study-of-the-reaction-mechanism-of-human-%C3%AE-ketoacyl-reductase
#1
Fabiola E Medina, Rui P P Neves, Maria J Ramos, Pedro A Fernandes
Human fatty acid synthase (hFAS) is a multifunctional enzyme involved in a wide diversity of biological functions. For instance, it is a precursor of phospholipids and other complex processes such as the de novo synthesis of long chain fatty acid. Human FAS is also a component of biological membranes and it is implicated in the overexpression of several types of cancers. In this work, we describe the catalytic mechanism of β-ketoreductase (KR), which is a catalytic domain of the hFAS enzyme that catalyzes the reduction of β-ketoacyl to β-hydroxyacyl with the concomitant oxidation of the NADPH cofactor...
December 1, 2016: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/27874952/nox1-promotes-colon-cancer-cell-metastasis-via-activation-of-the-adam17-pathway
#2
H-P Wang, X Wang, L-F Gong, W-J Chen, Z Hao, S-W Feng, Y-B Wu, T Ye, Y-K Cai
OBJECTIVE: Reactive oxygen species (ROS) generated by endogenous metabolic enzymes are involved in a variety of pathology processes, including cancer. In particular, superoxide-generating NADPH oxidase 1 (Nox1), a member of Nox enzyme family, is highly expressed in the colon tissue and has been implicated in physiological and pathophysiological states of colon cancer. However, the underlying molecular mechanism of Nox1 in the regulation of colon cancer progression remains largely unknown...
November 2016: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/27869172/a-redox-state-dictated-signalling-pathway-deciphers-the-malignant-cell-specificity-of-cd40-mediated-apoptosis
#3
C J Dunnill, K Ibraheem, A Mohamed, J Southgate, N T Georgopoulos
CD40, a member of the tumour necrosis factor receptor (TNFR) superfamily, has the capacity to cause extensive apoptosis in carcinoma cells, while sparing normal epithelial cells. Yet, apoptosis is only achieved by membrane-presented CD40 ligand (mCD40L), as soluble receptor agonists are but weakly pro-apoptotic. Here, for the first time we have identified the precise signalling cascade underpinning mCD40L-mediated death as involving sequential TRAF3 stabilisation, ASK1 phosphorylation, MKK4 (but not MKK7) activation and JNK/AP-1 induction, leading to a Bak- and Bax-dependent mitochondrial apoptosis pathway...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27864022/shikonin-inhibits-gefitinib-resistant-non-small-cell-lung-cancer-by-inhibiting-trxr-and-activating-the-egfr-proteasomal-degradation-pathway
#4
Xia Li, Xing-Xing Fan, Ze-Bo Jiang, Wings Ty Loo, Xiao-Jun Yao, Elaine Lai-Han Leung, Louis Wc Chow, Liang Liu
Non-small cell lung cancer (NSCLC) is the dominant type of lung cancer. Molecular targeting has highly improved the treatment efficacy of lung cancer, but new challenges have emerged, such as gefitinib-resistance and cancer recurrence. Therefore, new chemotherapeutic agents and treatment strategies are urgently needed. Shikonin is the main active component of a Chinese medicinal plant 'Zi Cao', which has been shown to exhibit powerful anti-cancer activity in certain types of cancer; however, its activity in gefitinib-resistant lung cancer has never been addressed...
November 15, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27862460/intracellular-cysteine-oxidation-is-modulated-by-aquaporin-8-mediated-hydrogen-peroxide-channeling-in-leukaemia-cells
#5
Francesco Vieceli Dalla Sega, Cecilia Prata, Laura Zambonin, Cristina Angeloni, Benedetta Rizzo, Silvana Hrelia, Diana Fiorentini
The modulation of H2 O2 production by NADPH oxidase (Nox), on vascular endothelial growth factor (VEGF) stimulation, affects the redox signaling linked to cancer cell proliferation. H2 O2 signal transduction involves reversible oxidation of thiol proteins, leading to the formation of cysteine sulfenic acids, responsible for the temporary inactivation of many phosphatases. These events imply that H2 O2 reaches its intracellular targets. As Aquaporin-8 (AQP8) has been demonstrated to funnel Nox-produced H2 O2 across the plasma membrane, this study aims to elucidate the role of AQP8 in the redox signaling occurring in human leukaemia B1647 cells that constitutively produce VEGF...
November 15, 2016: BioFactors
https://www.readbyqxmd.com/read/27858292/cisplatin-toxicity-in-dorsal-root-ganglion-neurons-is-relieved-by-meclizine-via-diminution-of-mitochondrial-compromise-and-improved-clearance-of-dna-damage
#6
Murat F Gorgun, Ming Zhuo, Ella W Englander
Chemotherapy-induced neurotoxicity of peripheral nervous system (PNS) hinders efficacy of cancer treatments. Mechanisms initiating PNS injury by anticancer drugs are incompletely understood delaying development of effective management strategies. To understand events triggered in PNS by cancer drugs, we exposed dorsal root ganglion (DRG) neurons to cisplatin, a drug from platinum-based class of chemotherapeutics frequently implicated in peripheral neuropathies. While cisplatin enters cancer cells and forms cisplatin/DNA crosslinks that block cell proliferation, circulating cisplatin can also reach the PNS and produce crosslinks that impede critical DNA transactions in postmitotic neurons...
November 17, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27835923/ros-no-mediated-inter-organ-communication-in-skeletal-muscle-wasting-diseases
#7
Lucia Maria Leitner, Rebecca June Wilson, Zhen Yan, Axel Gödecke
SIGNIFICANCE: Cachexia is defined as a complex metabolic syndrome associated with underlying illness and a loss of muscle with or without loss of fat mass. This disease is associated with high incidence with chronic diseases such as heart failure, cancer, chronic obstructive pulmonary disease, AIDS, among others. Since there is currently no effective treatment available, cachectic patients have a poor prognosis. Elucidation of the underlying mechanisms is therefore an important medical task...
November 11, 2016: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/27811150/serine-synthesis-helps-hypoxic-cancer-stem-cells-regulate-redox
#8
Debangshu Samanta, Gregg L Semenza
Phosphoglycerate dehydrogenase (PHGDH) is the metabolic enzyme responsible for shunting the glycolytic intermediate 3-phosphoglycerate to the serine synthesis pathway. In breast cancer and several other types of cancer, increased PHGDH expression is associated with patient mortality. Early studies focused on the role of PHGDH in promoting cell proliferation in the small percentage of breast cancers with PHGDH gene amplification. However, recent studies have revealed a critical role for PHGDH and downstream enzymes of the serine synthesis pathway and one carbon metabolism in NADPH production and the maintenance of redox homeostasis, which are required for enrichment of breast cancer stem cells in response to hypoxia or chemotherapy...
November 3, 2016: Cancer Research
https://www.readbyqxmd.com/read/27789379/a-new-label-free-screen-for-steroid-5%C3%AE-reductase-inhibitors-using-lc-ms
#9
Jukkarin Srivilai, Karma Rabgay, Nantaka Khorana, Neti Waranuch, Nitra Nuengchamnong, Kornkanok Ingkaninan
Steroid 5α-reductase (S5αR) plays an important role in metabolizing testosterone into active androgen dihydrotestosterone (DHT) which is involved in many androgen dependent disorders, such as androgenic alopecia, benign prostatic hyperplasia and acne. The method for screening for S5αR inhibition is key in finding new antagonists. In this study, the label-free S5αR inhibitory assay using LC-MS was developed. S5αR type 1 enzyme was obtained from LNCaP prostate cancer cells. The enzymatic assay was optimised for enzyme-substrate (testosterone) concentration, NADPH-cofactor concentration, solvent tolerance, enzyme activity stability and incubation time...
October 24, 2016: Steroids
https://www.readbyqxmd.com/read/27769111/cytochrome-p450-mediated-bioactivation-of-saracatinib
#10
Jiaming Chen, Ying Peng, Jiang Zheng
Saracatinib, is a highly selective Src kinase inhibitor against all Src kinase family members and has demonstrated anti-cancer effects in preclinical models. Unfortunately, it has shown multiple adverse effects during its clinical trials, along with time-dependent inhibition of P450 enzymes. The major objective of this study was to identify reactive metabolites of saracatinib in vitro and in vivo. Four oxidative metabolites (M1-M4) were detected in rat and human liver microsomal incubation systems after exposure to saracatinib...
October 21, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27765370/resveratrol-piperine-and-apigenin-differ-in-their-nadph-oxidase-inhibitory-and-reactive-oxygen-species-scavenging-properties
#11
Scott Whitehouse, Pei-Lin Chen, Anna L Greenshields, Mat Nightingale, David W Hoskin, Karen Bedard
BACKGROUND: Many plant-derived chemicals have been studied for their potential benefits in ailments including inflammation, cancer, neurodegeneration, and cardiovascular disease. The health benefits of phytochemicals are often attributed to the targeting of reactive oxygen species (ROS). However, it is not always clear whether these agents act directly as antioxidants to remove ROS, or whether they act indirectly by blocking ROS production by enzymes such as NADPH oxidase (NOX) enzymes, or by influencing the expression of cellular pro- and anti- oxidants...
November 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/27758112/pml-a-protein-at-the-cross-road-of-oxidative-stress-and-metabolism
#12
Sarah Tessier, Natalia Martin-Martin, Hugues de Thé, Arkaitz Carracedo, Valerie Lallemand-Breitenbach
SIGNIFICANCE: Cellular metabolic activity impacts on the production of reactive oxygen species (ROS), both positively through mitochondrial oxidative processes and negatively by promoting the production of reducing agents (including NADPH and reduced glutathione). A defined metabolic state in cancer cells is critical for cell growth and long-term self-renewal, and such state is intrinsically associated to redox balance. Promyelocytic leukemia protein (PML) regulates several biological processes, at least in part through its ability to control the assembly of PML Nuclear Bodies (PML NBs)...
October 19, 2016: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/27756874/mechanism-of-melanoma-cells-selective-apoptosis-induced-by-a-photoactive-nadph-analogue
#13
Florian Rouaud, Jean-Luc Boucher, Anny Slama-Schwok, Stéphane Rocchi
Melanoma is one of the most lethal cancers when it reaches a metastatic stage. Despite the spectacular achievements of targeted therapies (BRAF inhibitors) or immuno-therapies (anti-CTLA4 or anti-PD1), most patients with melanoma will need additional treatments. Here we used a photoactive NADPH analogue called NS1 to induce cell death by inhibition of NADPH oxidases NOX in melanoma cells, including melanoma cells isolated from patients. In contrast, healthy melanocytes growth was unaffected by NS1 treatment...
October 14, 2016: Oncotarget
https://www.readbyqxmd.com/read/27755120/glucose-6-phosphate-dehydrogenase-and-the-kidney
#14
Netanya Y Spencer, Robert C Stanton
PURPOSE OF REVIEW: Glucose 6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway. G6PD is the main source of the essential cellular reductant, NADPH. The purpose of this review is to describe the biochemistry of G6PD and NADPH, cellular factors that regulate G6PD, normal physiologic roles of G6PD, and the pathogenic role altered G6PD/NADPH plays in kidney disease. RECENT FINDINGS: NADPH is required for many essential cellular processes such as the antioxidant system, nitric oxide synthase, cytochrome p450 enzymes, and NADPH oxidase...
January 2017: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/27743884/peptide-screen-identifies-a-new-nadph-oxidase-inhibitor-impact-on-cell-migration-and-invasion
#15
Mohamed Mousslim, Alessandra Pagano, Nicolas Andreotti, Françoise Garrouste, Sylvie Thuault, Vincent Peyrot, Fabrice Parat, José Luis, Marcel Culcasi, Sophie Thétiot-Laurent, Sylvia Pietri, Jean-Marc Sabatier, Hervé Kovacic
The NADPH oxidase proteins catalyse the formation of superoxide anion which act as signalling molecules in physiological and pathological processes. Nox1-dependent NADPH oxidase is expressed in heart, lung, colon, blood vessels and brain. Different strategies involving Nox1 inhibition based on diphenylene iodonium derivatives are currently tested for colorectal cancer therapy. Here, after peptides screening on Nox1-dependent NADPH oxidase assay in HT-29 cells, we identify a peptide (referred to as NF02), cell-active, that potently block Nox1-dependent reactive oxygen species generation...
October 12, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27740521/predictive-role-blvra-mrna-expression-in-hepatocellular-cancer
#16
Kristy Na Kubícková, Iva Subhanová, Renáta Konícková, Linda Matousová, Petr Urbánek, Hana Parobková, Martin Kupec, Jirí Pudil, Libor Vítek
:  Introduction and aim. Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor. It is primarily caused by hepatic cirrhosis or chronic viral hepatitis. Hepatic carcinogenesis is associated with increased oxidative stress. Thus, the aim of our study was to assess expression of the genes involved in the homeostasis of oxidative stress in patients with HCC. MATERIAL AND METHODS: The study was performed on 32 patients with primary HCC (verified by liver histology in 29 patients) and 27 control subjects (in 11 subjects, liver histology was available either with no or minimal changes in the liver tissue)...
November 2016: Annals of Hepatology
https://www.readbyqxmd.com/read/27739027/an-indispensable-role-of-cpt-1a-to-survive-cancer-cells-during-energy-stress-through-rewiring-cancer-metabolism
#17
Jingtao Luo, Yun Hong, Xiaoan Tao, Xi Wei, Lun Zhang, Qiang Li
Unlike normal cells, cancer cells are recently identified to rely on aerobic glycolysis for energy production called the Warburg effect. Several attempts are being made to target this metabolic reprogramming pathway in treating cancers; however, the successful rate is very limited. In this study, we investigated the functional roles of fatty acid oxidation key enzyme carnitine palmitoyl transferase 1a (CPT-1a), during the metabolic programming of pancreatic ductal adenocarcinoma (PDAC) cells induced by glucose deprivation...
October 13, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/27716777/thioredoxin-inhibitors-attenuate-platelet-function-and-thrombus-formation
#18
Clive Metcalfe, Anjana Ramasubramoni, Giordano Pula, Matthew T Harper, Stuart J Mundell, Carmen H Coxon
Thioredoxin (Trx) is an oxidoreductase with important physiological function. Imbalances in the NADPH/thioredoxin reductase/thioredoxin system are associated with a number of pathologies, particularly cancer, and a number of clinical trials for thioredoxin and thioredoxin reductase inhibitors have been carried out or are underway. Due to the emerging role and importance of oxidoreductases for haemostasis and the current interest in developing inhibitors for clinical use, we thought it pertinent to assess whether inhibition of the NADPH/thioredoxin reductase/thioredoxin system affects platelet function and thrombosis...
2016: PloS One
https://www.readbyqxmd.com/read/27711204/metabolic-response-to-nad-depletion-across-cell-lines-is-highly-variable
#19
Yang Xiao, Mandy Kwong, Anneleen Daemen, Marcia Belvin, Xiaorong Liang, Georgia Hatzivassiliou, Thomas O'Brien
Nicotinamide adenine dinucleotide (NAD) is a cofactor involved in a wide range of cellular metabolic processes and is a key metabolite required for tumor growth. NAMPT, nicotinamide phosphoribosyltransferase, which converts nicotinamide (NAM) to nicotinamide mononucleotide (NMN), the immediate precursor of NAD, is an attractive therapeutic target as inhibition of NAMPT reduces cellular NAD levels and inhibits tumor growth in vivo. However, there is limited understanding of the metabolic response to NAD depletion across cancer cell lines and whether all cell lines respond in a uniform manner...
2016: PloS One
https://www.readbyqxmd.com/read/27706944/phytochemical-inhibition-of-multidrug-resistance-protein-1-as-a-therapeutic-strategy-for-hemangioendothelioma
#20
Ayan Biswas, Emma C Clark, Chandan K Sen, Gayle Gordillo
: Hemangiomas are endothelial cell tumors and the most common soft tissue tumors in infants. They frequently cause deformity and can cause death. Current pharmacologic therapies have high-risk side effect profiles, which limit the number of children that receive treatment. AIMS: The objectives of this work were to identify the mechanisms through which standardized berry extracts can inhibit endothelial cell tumor growth and test these findings in vivo. RESULTS: EOMA cells are a validated model that generates endothelial cell tumors when injected subcutaneously into syngeneic (129P/3) mice...
October 5, 2016: Antioxidants & Redox Signaling
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