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https://www.readbyqxmd.com/read/29156836/the-role-of-rak-in-the-regulation-of-stability-and-function-of-brca1
#1
Jung-Lye Kim, Geun-Hyoung Ha, Loredana Campo, Mitchell F Denning, Tarun B Patel, Clodia Osipo, Shiaw-Yih Lin, Eun-Kyoung Breuer
BRCA1 is an important player in the DNA damage response signaling, and its deficiency results in genomic instability. A complete loss or significantly reduced BRCA1 protein expression is often found in sporadic breast cancer cases despite the absence of genetic or epigenetic aberrations, suggesting the existence of other regulatory mechanisms controlling BRCA1 protein expression. Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156777/patients-with-nsclc-may-display-a-low-ratio-of-p-t790m-vs-activating-egfr-mutations-in-plasma-at-disease-progression-implications-for-personalised-treatment
#2
Marzia Del Re, Paola Bordi, Iacopo Petrini, Eleonora Rofi, Francesca Mazzoni, Lorenzo Belluomini, Enrico Vasile, Giuliana Restante, Francesco Di Costanzo, Alfredo Falcone, Antonio Frassoldati, Ron H N van Schaik, Christi M J Steendam, Antonio Chella, Marcello Tiseo, Riccardo Morganti, Romano Danesi
Introduction: NSCLC harboring activating mutations of EGFR is highly sensitive to first-line EGFR-tyrosine kinase inhibitors (TKIs), but drug resistance depending on the EGFR mutation p.T790M will occur in about 50-60% of patients. Detailed information on the amount of p.T790M plasmatic level associated with resistance to EGFR-TKIs and guidance to treatment with p.T790M-effective TKI depending on these levels, is lacking. Methods: This study enrolled p.T790M-positive patients (n=49) affected by EGFR-mutated NSCLC at progression to first-line EGFR-TKIs and, in selected cases (n=5), after second-line treatment with osimertinib...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156606/synthesis-and-in-vitro-cytotoxicity-of-the-4-halogenoanilino-6-bromoquinazolines-and-their-6-4-fluorophenyl-substituted-derivatives-as-potential-inhibitors-of-epidermal-growth-factor-receptor-tyrosine-kinase
#3
Malose Jack Mphahlele, Hugues K Paumo, Yee Siew Choong
Series of the 2-unsubstituted and 2-(4-chlorophenyl)-substituted 4-anilino-6-bromoquinazolines and their 6-(4-fluorophenyl)-substituted derivatives were evaluated for in vitro cytotoxicity against MCF-7 and HeLa cells. The 2-unsubstituted 4-anilino-6-bromoquinazolines lacked activity, whereas most of their 2-(4-chlorophenyl) substituted derivatives were found to exhibit significant cytotoxicity and selectivity against HeLa cells. Replacement of bromine with 4-fluorophenyl group for the 2-unsubstituted 4-anilinoquinazolines resulted in superior activity against HeLa cells compared to Gefitinib...
November 20, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/29156373/mitochondria-targeted-ubiquinone-mitoq-enhances-acetaldehyde-clearance-by-reversing-alcohol-induced-posttranslational-modification-of-aldehyde-dehydrogenase-2-a-molecular-mechanism-of-protection-against-alcoholic-liver-disease
#4
Liuyi Hao, Qian Sun, Wei Zhong, Wenliang Zhang, Xinguo Sun, Zhanxiang Zhou
Alcohol metabolism in the liver generates highly toxic acetaldehyde. Breakdown of acetaldehyde by aldehyde dehydrogenase 2 (ALDH2) in the mitochondria consumes NAD(+) and generates reactive oxygen/nitrogen species, which represents a fundamental mechanism in the pathogenesis of alcoholic liver disease (ALD). A mitochondria-targeted lipophilic ubiquinone (MitoQ) has been shown to confer greater protection against oxidative damage in the mitochondria compared to untargeted antioxidants. The present study aimed to investigate if MitoQ could preserve mitochondrial ALDH2 activity and speed up acetaldehyde clearance, thereby protects against ALD...
November 11, 2017: Redox Biology
https://www.readbyqxmd.com/read/29156306/effect-of-microcystins-on-root-growth-oxidative-response-and-exudation-of-rice-oryza-sativa
#5
Qing Cao, Richard R Rediske, Lei Yao, Liqiang Xie
A 30 days indoor hydroponic experiment was carried out to evaluate the effect of microcystins (MCs) on rice root morphology and exudation, as well as bioaccumulation of MCs in rice. MCs were bioaccumulated in rice with the greatest concentrations being observed in the leaves (113.68μgg(-1) Fresh weight (FW)) when exposed to 500μgL(-1) MCs. Root activity at 500μgL(-1) decreased 37%, compared to the control. MCs also induced disruption of the antioxidant system and lipid peroxidation in rice roots. Root growth was significantly inhibited by MCs...
November 17, 2017: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/29156201/which-new-agents-will-be-incorporated-into-frontline-therapy-in-acute-myeloid-leukemia
#6
REVIEW
Richard M Stone
For 4 decades, new agents had not been permanently approved for use in treating acute myeloid leukemia (AML). The long dry spell was broken in 2017, however, with the approval of several agents: midostaurin for addition to chemotherapy in mutant FLT3 patients undergoing intensive chemotherapy, enasidenib in advanced mutant IDH2 patients, CPX-351 in secondary AML patients, and gemtuzumab ozogamicin in conjunction with standard chemotherapy in AML. This review surveys the use of tyrosine kinase inhibitors to treat patients with mutant FLT3 AML, mutant KIT AML, as well as IDH inhibitors and explores some questions regarding their integration into the treatment armamentarium for AML...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29155585/allosteric-inhibitors-of-shp2-with-therapeutic-potential-for-cancer-treatment
#7
Jingjing Xie, Xiaojia Si, Shoulai Gu, Mingliang Wang, Jian Shen, Haoyan Li, Jian Shen, Dan Li, Yanjia Fang, Cong Liu, Jidong Zhu
SHP2, a cytoplasmic protein-tyrosine phosphatase encoded by the PTPN11 gene, is involved in multiple cell signaling processes including Ras/MAPK and Hippo/YAP pathways. SHP2 has been shown to contribute to the progression of a number of cancer types including leukemia, gastric and breast cancer. It also regulates T-cell activation by interacting with inhibitory immune checkpoint receptors such as the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA). Thus, SHP2 inhibitors have drawn great attention by both inhibiting tumor cell proliferation and activating T cell immune responses toward cancer cells...
November 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29155197/dyrk2-mediated-the-release-of-proinflammatory-cytokines-in-lps-induced-bv2-cells
#8
Li Xu, Yuxiang Sun, Mengmeng Li, Xin Ge
NF-κB pathway and p38MAPK (p38mitogen-activated protein kinase) pathway have been shown to play a key role in neuroinflammation, however, the phosphorylation modification is an important process that affects the activation of above pathways. Dual-specificity tyrosine-phosphorylation-regulated kinase 2(Dyrk2), as a phosphokinase that can phosphorylate signal molecules, has been demonstrated to regulate Type I Interferon(TIF) by promoting ser527 phosphorylation of TBK1. Therefore, to investigate the role of Dyrk2 in neuroinflammation, we analyzed the effect of Dyrk2 on LPS-induced the activation of microglia...
November 16, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29155093/histone-acetylation-of-oligodendrocytes-protects-against-white-matter-injury-induced-by-inflammation-and-hypoxia-ischemia-through-activation-of-bdnf-trkb-signaling-pathway-in-neonatal-rats
#9
Jichong Huang, Li Zhang, Yi Qu, Yan Zhou, Jianghu Zhu, Yafei Li, Tingting Zhu, Fengyan Zhao, Jun Tang, Dezhi Mu
The major pathological damage in encephalopathy of prematurity is white matter injury (WMI). Perinatal hypoxic-ischemia (HI) and inflammation are two major risk factors in the development of WMI. To study the cellular and molecular mechanisms of WMI, we set up a WMI model using lipopolysaccharide-sensitized HI injury in 2-day postnatal rats. Immunofluorescence staining was used to measure the expression of acetylated histone H3 (AH3) in oligodendrocytes, the target cells of WMI; the oligodendrocyte protein markers, NG2, O4, MBP, PLP, and MAG, were detected at different developmental stages...
November 16, 2017: Brain Research
https://www.readbyqxmd.com/read/29155039/perinatal-nicotine-exposure-increases-obesity-susceptibility-by-peripheral-leptin-resistance-in-adult-female-rat-offspring
#10
Wan-Xia Zhang, Yin-Ping Li, Jie Fan, Hui-Jian Chen, Gai-Ling Li, Yan-Qiong Ouyang, You-E Yan
Maternal nicotine (NIC) exposure causes overweight, hyperleptinemia and metabolic disorders in adult offspring. Our study aims to explore the underlying mechanism of perinatal NIC exposure increases obesity susceptibility in adult female rat offspring. In our model, we found that adult NIC-exposed females presented higher body weight and subcutaneous and visceral fat mass, as well as larger adipocytes, while no change was found in food intake. Serum profile showed a higher serum glucose, insulin and leptin levels in NIC-exposed females...
November 15, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29154817/cancer-stem-cell-like-population-is-preferentially-suppressed-by-egfr-tkis-in-egfr-mutated-pc-9-tumor-models
#11
Fan Yang, Yang Li, Bin Liu, Jiacong You, Qinghua Zhou
AIMS: Although the epidermal growth factor receptor (EGFR) and Wnt/β-catenin signaling systems synergistically regulate many essential developmental and regenerative processes in lung cancer, the mechanisms of their crosstalk remain poorly defined. Our study aimed to investigate an interaction between EGFR and the β-catenin signal. RESULTS: In this study, we described a potent activation of β-catenin by EGFR, which is dependent of the PtdIns3K/AKT pathway. We found EGF activated β-catenin signaling via phosphorylation of EGFR and AKT in EGFR-mutated PC-9 lung cancer cells...
November 14, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/29154500/structure-activity-studies-of-peptidomimetics-based-on-kinase-inhibitory-region-of-suppressors-of-cytokine-signaling-1
#12
Sara La Manna, Laura Lopez-Sanz, Marilisa Leone, Paola Brandi, Pasqualina Liana Scognamiglio, Giancarlo Morelli, Ettore Novellino, Carmen Gomez-Guerrero, Daniela Marasco
Suppressors of Cytokine Signaling (SOCS) proteins are negative regulators of JAK proteins that are receptor-associated tyrosine kinases, which play key roles in the phosphorylation and subsequent activation of several transcription factors named STATs. Unlike the other SOCS proteins, SOCS1 and 3 show, in the N-terminal portion, a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Drug discovery processes of compounds based on KIR sequence demonstrated promising in functional in vitro and in inflammatory animal models and we recently developed a peptidomimetic called PS5, as lead compound...
November 20, 2017: Biopolymers
https://www.readbyqxmd.com/read/29154227/generation-of-integration-free-induced-pluripotent-stem-cell-line-njmui001-a-from-a-phenylketonuria-patient
#13
Tianhui Xu, Dong Liang, Jingjing Zhang, Xiuqing Ji, Huanran Hu, Yun Sun, Tao Jiang, Xia Wang, Ping Hu, Zhengfeng Xu
PKU is a prevalent type of inherited metabolic disease, caused by the defective phenylalanine metabolism. In most PKU cases, mutations in the PAH gene could be found. Dysfunction of this hepatic enzyme will lead to diverse clinical symptoms due to a failure in converting phenylalanine into tyrosine. Here, we report an integration-free human induced pluripotent stem cell line (NJMUi001-A) generated from peripheral blood mononuclear cells of a PKU patient by using Sendai virus. This iPS cell line has characteristics of pluripotent stem cells and can be used as a useful tool for the investigation of this inherited metabolic disease...
November 10, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29154193/fundamentals-on-the-biochemistry-of-peroxynitrite-and-protein-tyrosine-nitration
#14
REVIEW
Silvina Bartesaghi, Rafael Radi
In this review we provide an analysis of the biochemistry of peroxynitrite and tyrosine nitration. Peroxynitrite is the product of the diffusion-controlled reaction between superoxide (O2(•)(-)) and nitric oxide ((•)NO). This process is in competition with the enzymatic dismutation of O2(•-) and the diffusion of (•)NO across cells and tissues and its reaction with molecular targets (e.g. guanylate cyclase). Understanding the kinetics and compartmentalization of the O2(•-) / (•)NO interplay is critical to rationalize the shift of (•)NO from a physiological mediator to a cytotoxic intermediate...
September 19, 2017: Redox Biology
https://www.readbyqxmd.com/read/29154090/proliferative-and-metastatic-roles-for-phospholipase-d-in-mouse-models-of-cancer
#15
REVIEW
Eric Roth, Michael A Frohman
Phospholipase D (PLD) activity has been proposed to facilitate multiple steps in cancer progression including growth, metabolism, angiogenesis, and mobility. The canonical enzymes PLD1 and PLD2 enact their diverse effects through hydrolyzing the membrane lipid phosphatidylcholine to generate the second messenger and signaling lipid phosphatidic acid (PA). However, the widespread expression of PLD1 and PLD2 in normal tissues and the additional distinct enzymatic mechanisms through which PA can be generated have produced uncertainty regarding the optimal settings in which PLD inhibition might ameliorate cancer...
November 14, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/29153923/macrophages-sensing-oxidized-damps-reprogram-their-metabolism-to-support-redox-homeostasis-and-inflammation-through-a-tlr2-syk-ceramide-dependent-mechanism
#16
Vlad Serbulea, Clint M Upchurch, Katelyn W Ahern, Gael Bories, Paxton Voigt, Dory E DeWeese, Akshaya K Meher, Thurl E Harris, Norbert Leitinger
OBJECTIVE: Macrophages control tissue homeostasis and inflammation by sensing and responding to environmental cues. However, the metabolic adaptation of macrophages to oxidative tissue damage and its translation into inflammatory mechanisms remains enigmatic. METHODS: Here we identify the critical regulatory pathways that are induced by endogenous oxidation-derived DAMPs (oxidized phospholipids, OxPL) in vitro, leading to formation of a unique redox-regulatory metabolic phenotype (Mox), which is strikingly different from conventional classical or alternative macrophage activation...
November 7, 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29153675/sflt-1-and-soluble-endoglin-concentrations-in-serum-vs-plasma-in-preterm-preeclampsia-are-they-interchangeable-for-biomarker-studies
#17
Fiona Brownfoot, Tu'uhevaha Kaitu'u-Lino, Sally Beard, Stephen Tong, Natalie Hannan
Soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are increased in the circulation of women with preeclampsia. We examined whether they differ in concentration between plasma and serum samples. Maternal blood was collected and processed for serum and plasma, from 28 women with preterm preeclampsia and 18 gestation matched controls (<34weeks). Significantly higher sFlt-1 was detected in preeclamptic serum compared to plasma. Significantly higher levels of sENG were identified in serum compared to plasma from control pregnancies...
October 2017: Pregnancy Hypertension
https://www.readbyqxmd.com/read/29153530/physicochemical-and-sensory-properties-of-yogurts-containing-sacha-inchi-plukenetia-volubilis-l-seeds-and-%C3%AE-glucans-from-ganoderma-lucidum
#18
Ana-Milena Vanegas-Azuero, Luis-Felipe Gutiérrez
Dairy products have been widely used for adding various biomolecules with the aim of improving their functional properties and health benefits. In this study, the physicochemical properties and sensory acceptance of yogurts enriched with sacha inchi (Plukenetia volubilis) seeds (SIS) and β-glucans from Ganoderma lucidum (BGGL) were investigated. The angiotensin-converting enzyme-inhibitory activity of some yogurt samples was also evaluated. Yogurts were produced from reconstituted skim milk powder, and SIS (4% wt/wt) and BGGL were added at different concentrations (0-1...
November 15, 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/29153023/-bone-metabolism-in-adults-with-phenylketonuria-hungarian-data
#19
András Gellért Barta, Csaba Sumánszki, Péter Reismann
INTRODUCTION: Patients with phenylketonuria have lower bone mineral density compared to healthy people, however, the ethiology of these alterations is not clear. Hungarian data were missing in this topic. AIM: The main aim of our study was to survey the correlation between metabolic control and change of bone mineral density in early treated Hungarian adult patients with phenylketonuria. METHOD: In this monocentric study bone mineral density of 59 adult PKU patients have been repeatedly measured in a 4-year interval using dual-energy X-ray absorptiometry...
November 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/29152652/effect-of-wnt1-and-wnt5a-on-the-development-of-dopaminergic-neurons-and-toxicity-induced-by-combined-exposure-to-paraquat-and-maneb-during-gestation-and-lactation
#20
Jing Ma, Cui Huang, Kun Ma, Yan-Ping Wu, Bai-Xiang Li, Yan Sun
Paraquat (PQ) and maneb (MB) are widely used herbicides. Wingless (Wnt) proteins serve a role in the development and differentiation of dopaminergic neurons. Previous studies demonstrated that combined exposure to PQ and MB damages dopaminergic neurons in the midbrain. Effects of PQ and MB exposure on midbrain Wnt proteins have also been previously reported. In the present study, from the 5th day of gestation to weaning of the offspring, pregnant Sprague‑Dawley rats were administrated saline, or PQ and MB at two different doses: high, 15 mg/kg body weight PQ + 45 mg/kg body weight MB; or low, 10 mg/kg body weight PQ + 30 mg/kg body weight MB...
October 19, 2017: Molecular Medicine Reports
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