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https://www.readbyqxmd.com/read/29288045/elevated-nuclear-phosphatase-and-tensin-homolog-pten-and-altered-insulin-signaling-in-substantia-nigral-region-of-patients-with-parkinson-s-disease
#1
Sathiya Sekar, Changiz Taghibiglou
Studies showed that 50-80% of Parkinson's disease (PD) patients have been reported with abnormal glucose tolerance. Alterations in glucose and energy metabolism serve as the early molecular event in PD. Although evidences support that the insulin resistance plays a major role in motor and non-motor complications of PD, the underlying mechanism in the pathogenesis of PD is unclear. To address this issue, we investigated the alterations in major components of insulin signaling in nuclear fraction (NF) and whole tissue homogenate (TH) of substantia nigral (SN) region obtained from postmortem PD brain and their age-matched controls...
December 26, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29273202/modes-of-interaction-of-pleckstrin-homology-domains-with-membranes-towards-a-computational-biochemistry-of-membrane-recognition
#2
Fiona B Naughton, Antreas C Kalli, Mark S P Sansom
Pleckstrin homology (PH) domains mediate protein-membrane interactions by binding to phosphatidylinositol phosphate (PIP) molecules. The structural and energetic basis of selective PH-PIP interactions is central to understanding many cellular processes, yet the molecular complexities of the PH-PIP interactions are largely unknown. Molecular dynamics (MD) simulations using a coarse-grained model enables estimation of free energy landscapes for the interactions of 12 different PH domains with membranes containing PIP2 or PIP3, allowing us to obtain a detailed molecular energetic understanding of the complexities of the interactions of the PH domains with PIP molecules in membranes...
December 19, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29259786/necessity-to-evaluate-pi3k-akt-signalling-pathway-in-proarrhythmia
#3
REVIEW
Martin Ezeani, Sunday Elom
The incidence of QT prolongation and torsades de pointes is on the rise due to the use of cardiovascular and non-cardiovascular drugs. Robust efforts have been made and are still ongoing to understand the underlying mechanisms that can enhance or prevent the development of drug-induced proarrhythmia. A caveat in the use of antiarrhythmic drugs is the ability to obtain safe action potential prolongation therapeutic effects, through IKr blockade. This remains as yet completely unachievable, as blockers of the potassium channel have not provided complete safe measures...
2017: Open Heart
https://www.readbyqxmd.com/read/29242514/dna-damage-causes-rapid-accumulation-of-phosphoinositides-for-atr%C3%A2-signaling
#4
Yu-Hsiu Wang, Anushya Hariharan, Giulia Bastianello, Yusuke Toyama, G V Shivashankar, Marco Foiani, Michael P Sheetz
Phosphoinositide lipids (PPIs) are enriched in the nucleus and are accumulated at DNA damage sites. Here, we investigate roles of nuclear PPIs in DNA damage response by sequestering specific PPIs with the expression of nuclear-targeted PH domains, which inhibits recruitment of Ataxia telangiectasia and Rad3-related protein (ATR) and reduces activation of Chk1. PPI-binding domains rapidly (< 1 s) accumulate at damage sites with local enrichment of PPIs. Accumulation of PIP3 in complex with the nuclear receptor protein, SF1, at damage sites requires phosphorylation by inositol polyphosphate multikinase (IPMK) and promotes nuclear actin assembly that is required for ATR recruitment...
December 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/29231896/differential-expression-of-serum-micrornas-supports-cd4%C3%A2-%C2%BA-t-cell-differentiation-into-th2-th17-cells-in-severe-equine-asthma
#5
Alicja Pacholewska, Matthias F Kraft, Vincent Gerber, Vidhya Jagannathan
MicroRNAs (miRNAs) regulate post-transcriptional gene expression and may be exported from cells via exosomes or in partnership with RNA-binding proteins. MiRNAs in body fluids can act in a hormone-like manner and play important roles in disease initiation and progression. Hence, miRNAs are promising candidates as biomarkers. To identify serum miRNA biomarkers in the equine model of asthma we investigated small RNA derived from the serum of 34 control and 37 asthmatic horses. These samples were used for next generation sequencing, novel miRNA identification and differential miRNA expression analysis...
December 12, 2017: Genes
https://www.readbyqxmd.com/read/29211993/single-molecule-study-reveals-how-receptor-and-ras-synergistically-activate-pi3k%C3%AE-and-pip3-signaling
#6
Thomas C Buckles, Brian P Ziemba, Glenn R Masson, Roger L Williams, Joseph J Falke
Cellular pathways controlling chemotaxis, growth, survival, and oncogenesis are activated by receptor tyrosine kinases and small G-proteins of the Ras superfamily that stimulate specific isoforms of phosphatidylinositol-3-kinase (PI3K). These PI3K lipid kinases phosphorylate the constitutive lipid phosphatidylinositol-4,5-bisphosphate (PIP2) to produce the signaling lipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). Progress has been made in understanding direct, moderate PI3K activation by receptors. In contrast, the mechanism by which receptors and Ras synergistically activate PI3K to much higher levels remains unclear, and two competing models have been proposed: membrane recruitment versus activation of the membrane-bound enzyme...
December 5, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/29207200/effect-of-tw37-on-the-growth-of-h1975-egfr%C3%A2-tki%C3%A2-resistant-lung-cancer-cells-and-its-underlying-mechanisms
#7
Jixian Liu, Xinhuang Yao, Da Wu, Yiwang Ye, Qiang Wu, Suyue Liu, Hao Wu
Previous studies have suggested that the B‑cell lymphoma 2 (Bcl‑2) inhibitor, TW37, may induce apoptosis of the non‑small cell lung cancer cell line, H1975/epidermal growth factor receptor‑tyrosine kinase inhibitor (EGFR‑TKI), which exhibits secondary resistance to EGFR‑TKI. However, the effects of TW37 on H1975/EGFR‑TKI cells remain unclear. The aim of the present study was to investigate the effects of TW37 on the growth of H1975/EGFR‑TKI cells and explore the underlying mechanisms. An in vitro study was performed, whereby H1975/EGFR‑TKI cells were treated with serially increasing concentrations of TW37...
November 29, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29186690/growth-of-b-cell-receptor-microclusters-is-regulated-by-pip2-and-pip3-equilibrium-and-dock2-recruitment-and-activation
#8
Jing Wang, Liling Xu, Samina Shaheen, Sichen Liu, Wenjie Zheng, Xiaolin Sun, Zhanguo Li, Wanli Liu
The growth of B cell receptor (BCR) microclusters upon antigen stimulation drives B cell activation. Here, we show that PI3K-mediated PIP3 production is required for the growth of BCR microclusters. This growth is likely inhibited by PTEN and dependent on its plasma membrane binding and lipid phosphatase activities. Mechanistically, we find that PIP3-dependent recruitment and activation of a guanine nucleotide exchange factor, Dock2, is required for the sustained growth of BCR microclusters through remodeling of the F-actin cytoskeleton...
November 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/29155180/cell-membrane-dynamics-induction-using-optogenetic-tools
#9
Yoshibumi Ueda, Moritoshi Sato
Structures arising from actin-based cell membrane movements, including ruffles, lamellipodia, and filopodia, play important roles in a broad spectrum of cellular functions, such as cell motility, axon guidance in neurons, wound healing, and micropinocytosis. Previous studies investigating these cell membrane dynamics often relied on pharmacological inhibition, RNA interference, and constitutive active/dominant negative protein expression systems. However, such studies did not allow the modulation of protein activity at specific regions of cells, tissues, and organs in animals with high spatial and temporal precision...
November 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29141870/ig%C3%AE-ubiquitination-activates-pi3k-signals-required-for-endosomal-sorting
#10
Margaret Veselits, Azusa Tanaka, Yaoqing Chen, Keith Hamel, Malay Mandal, Matheswaran Kandasamy, Balaji Manicassamy, Shannon K O'Neill, Patrick Wilson, Roger Sciammas, Marcus R Clark
A wealth of in vitro data has demonstrated a central role for receptor ubiquitination in endocytic sorting. However, how receptor ubiquitination functions in vivo is poorly understood. Herein, we report that ablation of B cell antigen receptor ubiquitination in vivo uncouples the receptor from CD19 phosphorylation and phosphatidylinositol 3-kinase (PI3K) signals. These signals are necessary and sufficient for accumulating phosphatidylinositol (3,4,5)-trisphosphate (PIP3) on B cell receptor-containing early endosomes and proper sorting into the MHC class II antigen-presenting compartment (MIIC)...
November 15, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29141223/gradients-of-rac1-nanoclusters-support-spatial-patterns-of-rac1-signaling
#11
Amanda Remorino, Simon De Beco, Fanny Cayrac, Fahima Di Federico, Gaetan Cornilleau, Alexis Gautreau, Maria Carla Parrini, Jean-Baptiste Masson, Maxime Dahan, Mathieu Coppey
Rac1 is a small RhoGTPase switch that orchestrates actin branching in space and time and protrusion/retraction cycles of the lamellipodia at the cell front during mesenchymal migration. Biosensor imaging has revealed a graded concentration of active GTP-loaded Rac1 in protruding regions of the cell. Here, using single-molecule imaging and super-resolution microscopy, we show an additional supramolecular organization of Rac1. We find that Rac1 partitions and is immobilized into nanoclusters of 50-100 molecules each...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29138419/ivig-activates-fc%C3%AE-riib-ship1-pip3-pathway-to-stabilize-mast-cells-and-suppress-inflammation-after-ich-in-mice
#12
Gokce Yilmaz Akyol, Anatol Manaenko, Onat Akyol, Ihsan Solaroglu, Wing Mann Ho, Yan Ding, Jerry Flores, John H Zhang, Jiping Tang
Following intracerebral hemorrhage (ICH), the activation of mast cell contributes to brain inflammation and brain injury. The mast cell activation is negatively regulated by an inhibitory IgG-receptor. It's signals are mediated by SHIP (Src homology 2-containing inositol 5' phosphatase), in particular SHIP1, which activation leads to hydrolyzation of PIP3 (Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3, leading to the inhibition of calcium mobilization and to the attenuation of mast cell activation...
November 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29136761/galangin-inhibits-the-cell-progression-and-induces-cell-apoptosis-through-activating-pten-and-caspase-3-pathways-in-retinoblastoma
#13
Wen-Wei Zou, Su-Ping Xu
Retinoblastoma is reported as a rare cancer that occurs during childhood. Although several treatments are available for retinoblastoma, there is a need for alternative new treatment modalities for retinoblastoma with better safety and efficacy profile. Galangin (3,5,7-trihydroxyflavone), is a flavonoid compound, which is found in high concentration in lesser galangal. Galangin has been reported to have various bioactivities, including anti-inflammation, anti-oxidative stress and anti-cancer through various pathways...
November 6, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29117520/phosphorylated-calmodulin-promotes-pi3k-activation-by-binding-to-the-sh2-domains
#14
Mingzhen Zhang, Hyunbum Jang, Vadim Gaponenko, Ruth Nussinov
How calmodulin (CaM) acts in KRAS-driven cancers is a vastly important question. CaM binds to and stimulates PI3Kα/Akt signaling, promoting cell growth and proliferation. Phosphorylation of CaM at Tyr(99) (pY99) enhances PI3Kα activation. PI3Kα is a lipid kinase. It phosphorylates PIP2 to produce PIP3, to which Akt binds. PI3Kα has two subunits: the regulatory p85 and the catalytic p110. Here, exploiting explicit-solvent MD simulations we unveil key interactions between phosphorylated CaM (pCaM) and the two SH2 domains in the p85 subunit, confirm experimental observations, and uncover PI3Kα's mechanism of activation...
November 7, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/29113199/mir-214-targets-the-pten-mediated-pi3k-akt-signaling-pathway-and-regulates-cell-proliferation-and-apoptosis-in-ovarian-cancer
#15
Jing Liu, Weiyan Chen, Haiyan Zhang, Ting Liu, Lin Zhao
The present study aimed to investigate the potential role of microRNA (miR)-214 in targeting the phosphatase and tensin homolog (PTEN)-mediated phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in ovarian cancer (OC). The target gene of miR-214 was determined by luciferase reporter gene assay and was indicated to be PTEN. Human SK-OV-3 cells were transfected with a miR-214 inhibitor and a miR-214 mimic, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect relative expression of miR-214...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29111280/akt-activation-a-potential-strategy-to-ameliorate-insulin-resistance
#16
REVIEW
Zhengyi Zhang, Huadong Liu, Jiankang Liu
Insulin resistance is a hallmark of type 2 diabetes and obesity while the mechanism remains unclear. Current therapy to treat type 2 diabetes is metformin, the 5'-monophosphate-activated protein kinase (AMPK) activator, owing to the ability to augment peripheral glucose uptake. However, metformin also displays limitations, as AMPK activation remains intact and regular in most type 2 diabetes and metformin does not seem to facilitate peripheral insulin resistance. Evidence has shown that PI3K-Akt/PKB pathway could be induced via insulin and act as an important effector...
October 27, 2017: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/29035165/development-of-highly-sensitive-cell-based-akt-kinase-elisa-for-monitoring-pi3k-beta-activity-and-compound-efficacy
#17
Mahesh Yanamandra, Labanyamoy Kole, Archana Giri, Sayan Mitra
Phosphatidylinositol-3 kinase (PI3K) pathway regulates multiple cellular functions involving cell survival, growth, motility proliferation, apoptosis, and adhesion. These are deregulated in various diseases such as cancer, atherosclerosis, and inflammation. PI3Ks phosphorylate phosphatidylinositol 4,5-biphosphate (PIP2) yielding phosphatidylinositol 3, 4, 5 triphosphate (PIP3) which in turn activate AKT kinase (serine/threonine kinase), the central enzyme in regulation of metabolic functions. Due to their implications in disease pathophysiology, PI3K/AKT inhibitors became attractive targets for pharmaceutical industries...
October 16, 2017: Journal of Immunoassay & Immunochemistry
https://www.readbyqxmd.com/read/28901472/inositol-hexaphosphate-hydrolysate-competitively-binds-to-akt-to-inhibit-the-proliferation-of-colon-carcinoma
#18
Chen Chen, Fuguo Yang, Cuiping Liu, Lianhua Cui, Min Fu, Yang Song
Phytate, myto-inositol 1,2,3,4,5,6 hexaphosphate (IP6), is recognized as an anti-nutrition phytochemical for decades. Recently, numerous studies have indicated that IP6 and its hydrolysates could suppress colon oncogenesis. However, very little is known concerning the mechanism of IP6 hydrolysates in regulating colon oncogenesis. The aim of the present study was to identify the underlying relationship between IP6 hydrolysates and colon cancer. Three types of human colorectal cancer cells were utilized in the present study...
November 2017: Oncology Reports
https://www.readbyqxmd.com/read/28891094/regulation-of-the-tumor-suppressor-pten-by-natural-anticancer-compounds
#19
REVIEW
Do-Hee Kim, Jinyoung Suh, Young-Joon Surh, Hye-Kyung Na
The tumor suppressor phosphatase and tensin homologue (PTEN) has phosphatase activity, with phosphatidylinositol (3,4,5)-trisphosphate (PIP3), a product of phosphatidylinositol 3-kinase (PI3K), as one of the principal substrates. PTEN is a negative regulator of the Akt pathway, which plays a fundamental role in controlling cell growth, survival, and proliferation. Loss of PTEN function has been observed in many different types of cancer. Functional inactivation of PTEN as a consequence of germ-line mutations or promoter hypermethylation predisposes individuals to malignancies...
August 2017: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/28877984/%C3%AE-5%C3%AE-1-integrin-promotes-tension-dependent-mammary-epithelial-cell-invasion-by-engaging-the-fibronectin-synergy-site
#20
Y A Miroshnikova, G I Rozenberg, L Cassereau, M Pickup, J K Mouw, G Ou, K L Templeman, E-I Hannachi, K J Gooch, A L Sarang-Sieminski, A J García, V M Weaver
Tumors are fibrotic and characterized by abundant, remodeled, and cross-linked collagen that stiffens the extracellular matrix stroma. The stiffened collagenous stroma fosters malignant transformation of the tissue by increasing tumor cell tension to promote focal adhesion formation and potentiate growth factor receptor signaling through kinase. Importantly, collagen cross-linking requires fibronectin (FN). Fibrotic tumors contain abundant FN, and tumor cells frequently up-regulate the FN receptor α5β1 integrin...
November 1, 2017: Molecular Biology of the Cell
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