scholarly journals Blockage of Store-Operated Ca2+ Influx by Synta66 is Mediated by Direct Inhibition of the Ca2+ Selective Orai1 Pore

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2876 ◽  
Author(s):  
Linda Waldherr ◽  
Adela Tiffner ◽  
Deepti Mishra ◽  
Matthias Sallinger ◽  
Romana Schober ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Selective Inhibitor ◽  
Extracellular Loop ◽  
Direct Inhibition ◽  
Cell Progression ◽  
Drug Inhibition ◽  
And Migration ◽  
Dynamics Simulations ◽  
Soc Channels ◽  
Pore Blocker

The Ca2+ sensor STIM1 and the Ca2+ channel Orai1 that form the store-operated Ca2+ (SOC) channel complex are key targets for drug development. Selective SOC inhibitors are currently undergoing clinical evaluation for the treatment of auto-immune and inflammatory responses and are also deemed promising anti-neoplastic agents since SOC channels are linked with enhanced cancer cell progression. Here, we describe an investigation of the site of binding of the selective inhibitor Synta66 to the SOC channel Orai1 using docking and molecular dynamics simulations, and live cell recordings. Synta66 binding was localized to the extracellular site close to the transmembrane (TM)1 and TM3 helices and the extracellular loop segments, which, importantly, are adjacent to the Orai1-selectivity filter. Synta66-sensitivity of the Orai1 pore was, in fact, diminished by both Orai1 mutations affecting Ca2+ selectivity and permeation of Na+ in the absence of Ca2+. Synta66 also efficiently blocked SOC in three glioblastoma cell lines but failed to interfere with cell viability, division and migration. These experiments provide new structural and functional insights into selective drug inhibition of the Orai1 Ca2+ channel by a high-affinity pore blocker.

Computational studies of ice defects

2003 ◽  
Vol 81 (1-2) ◽  
pp. 325-332 ◽  
Author(s):  
P LM Plummer
Keyword(s):  
Defect Formation ◽  
Structural Evolution ◽  
Energy Difference ◽  
Electronic Energy ◽  
Energy Structure ◽  
Defect Site ◽  
And Migration ◽  
Dynamics Simulations ◽  
Small Clusters ◽  
Structure Calculations

Continuing our investigations of the energetics associated with defect formation and migration, both ab initio energy-structure calculations and molecular dynamics simulations are carried out on small clusters of water molecules containing one or more defects in hydrogen bonding. Previous studies in this series have identified structures containing defects that are stable at 0 K or that are transition states between such structures. However, results from this laboratory and elsewhere have shown that the energy required for the production or migration of a defect is more complex than merely the energy difference between the static structures. Cooperative motion of neighbors to the defect site can either increase or decrease the energy involved to produce or annihilate the defect. Thus, experimental measurements associated with the energy of defects in ice can differ substantially from those calculated using static models. By increasing the complexity of the model, the studies described in this report attempt to more realistically simulate a defect-containing ice system. The types of defects studied include ion and ion-pair defects. The initial structures are energetically stable — minima on the electronic energy surface — and contain one or more kinds of defects. Since the means and amount of energy injection can alter the migration path, the energy is introduced into the system in a variety of ways. The structural evolution of the ice system is then monitored as a function of time. PACS Nos.: 82.20Wt, 82.20Kh, 82.30Rs

scholarly journals Long Non-Coding RNA-DUXAP8 Regulates TOP2A in the Growth and Metastasis of Osteosarcoma via MicroRNA-635

2020 ◽  
Author(s):  
Ting Yang ◽  
Jian Ping Quo ◽  
Fan Li ◽  
Chao Xiu ◽  
Hua Wang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Human Cancer ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
High Morbidity ◽  
Real Time Quantitative Pcr ◽  
Diagnosis And Prognosis ◽  
Non Coding Rna ◽  
Cell Progression ◽  
And Migration

Abstract Purpose: Osteosarcoma (OS) is a malignant tumor disease with high morbidity and mortality in children and adolescents. Evidence indicates that long non-coding RNAs (lncRNAs) may be important players in human cancer progression, including OS. In this study, we identified the role of lnc-DUXAP8 in the development of OS.Materials and Methods: Expression of lncRNA DUXAP8 was determined by real-time quantitative PCR and Western blotting in OS tissues. Cell proliferation was evaluated using CCK8 and colony formation assay; Transwell assay was conducted to measure cell invasion. Cell migration was evaluated using Wound Healing assay. The binding site between the lnc-DUXAP8 and miR-635 RNAs was evaluated using a luciferase reporter assay. Results: The expression of the lnc-DUXAP8 was significantly upregulated in OS samples and OS cell lines compared to normal tissue. High expression of lncRNA DUXAP8 was associated with shorter overall survival. Knockdown of lncRNA DUXAP8 inhibited proliferation and migration, and invasion in OS cells. More importantly, mechanism investigation revealed that lncRNA DUXAP8 was predominantly acted as a competing endogenous RNA (ceRNA) in OS by regulating miR-635/ TOP2A axis. Conclusion: LncRNA DUXAP8 is upregulated in OS, and LncRNA DUXAP8 knockdown plays a vital anti-tumor role in OS cell progression through a miR-635/ TOP2A axis. Our study suggests that LncRNA DUXAP8 may be a novel, promising biomarker for diagnosis and prognosis of OS.

Abstract 187: Regulation of Vascular Smooth Muscle Cell (VSMC) Inflammation and Migration by the Pro-resolving Lipid Mediator Maresin-1 (mar1)

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Anuran Chatterjee ◽  
Robert Toy ◽  
Giorgio Mottola ◽  
Mian Chen ◽  
Michael S Conte
Keyword(s):  
Actin Polymerization ◽  
Inflammatory Responses ◽  
Oxidant Stress ◽  
Lipid Mediator ◽  
Monocyte Adhesion ◽  
Inflammatory Gene Expression ◽  
New Class ◽  
Tnf Α ◽  
And Migration ◽  
Inflammatory Molecules

Introduction Resolution of acute inflammation is regulated by endogenous lipid mediators derived from polyunsaturated fatty acids such as docosahexaenoic acid (DHA), however little is known about mechanisms of resolution in vascular injury. We investigated the effects of the DHA-derived mediator Mar1 on VSMC phenotype responses. Methods Primary human VSMCs were obtained from saphenous vein. VSMC were pretreated with Mar1 (10-100nM) then exposed to TNF-α (10ng/ml), and inflammatory responses assessed using a monocyte adhesion (U937) assay, expression of cell adhesion molecules and pro-inflammatory molecules (qPCR, western blot, ELISA), and production of superoxide (DHE). VSMC migration was measured in a transwell assay with PDGF-AB as the agonist, and cyotskeletal changes were assessed by actin-phalloidin staining. Results Mar-1 (100 nM) reduced U937 adhesion to TNF-stimulated VSMC, VCAM-1, and pro-inflammatory cytokine (IL-6, IL-8) expression. Superoxide production measured by DHE fluorescence was reduced by 57% (p=0.002) and Nox4 expression was markedly attenuated (43%, p=0.01). Mar-1 (0.01-100nM) induced rapid cytoskeletal changes with increased cell area, and reduced VSMC migration (76%, p=0.004) to PDGF-AB (50ng/ml; Figure). Conclusions Mar-1 attenuates TNF-α inflammatory activation of VSMC, with reduction in pro-inflammatory gene expression, oxidant stress, and monocyte adhesion. Mar-1 reduces actin polymerization and inhibits VSMC chemotaxis to PDGF. Pro-resolving mediators may represent a new class of endogenous vascular therapeutics.

Kinetic Monte Carlo Method

2006 ◽  
Author(s):  
Vasily Bulatov ◽  
Wei Cai
Keyword(s):  
Monte Carlo ◽  
Kinetic Monte Carlo ◽  
Dislocation Core ◽  
Dislocation Motion ◽  
Coarse Grained ◽  
Solid Thin Films ◽  
Finite Set ◽  
And Migration ◽  
Dynamics Simulations ◽  
Straight Segments

The PN model discussed in the preceding chapter is a continuum approach that requires some atomistic input to account for non-linear interactions in the dislocation core. In this chapter, we introduce yet another continuum model that uses atomistic input for a different purpose. The kinetic Monte Carlo (kMC) model does not consider any details of the core structure but instead focuses on dislocation motion on length and time scales far greater than those of the atomistic simulations. The model is especially effective for diamond-cubic semiconductors and other materials in which dislocation motion is too slow to be observed on the time scale of molecular dynamics simulations. The key idea of the kMC approach is to treat dislocation motion as a stochastic sequence of discrete rare events whose mechanisms and rates are computed within the framework of the transition state theory. Built around its unit mechanisms, the kMC model simulates dislocation motion and predicts dislocation velocity as a function of stress and temperature. This data then can be used to construct accurate mobility functions for dislocation dynamics simulations on still larger scales (Chapter 10). In this sense, kMC serves as a link between atomistic models and coarse-grained continuum models of dislocations. The kMC approach is most useful in situations where the system evolves through a stochastic sequence of events with only a few possible event types. The method has been used in a wide variety of applications other than dislocations. For example, the growth of solid thin films from vapor or in solution is known to proceed through attachment and diffusion of adatoms deposited on the surface. Based on a finite set of unit mechanisms of the motion of adatoms, kMC models accurately describe the kinetics of growth and the resulting morphology evolution of the epitaxial films [95, 96, 97]. Similar kMC models have been applied to dislocation motion in crystals with high lattice resistance, such as silicon. In these materials, dislocations consist of long straight segments interspersed with atomic-sized kinks, depicted schematically in Fig. 9.1(a) as short vertical segments. As was explained in Section 1.3, dislocation motion proceeds through nucleation and migration of kink pairs and can be described well by a kMC model.

scholarly journals Circular METRN RNA hsa_circ_0037251 Promotes Glioma Progression by Sponging miR-1229-3p and Regulating mTOR Expression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Qinchen Cao ◽  
Yonggang Shi ◽  
Xinxin Wang ◽  
Jing Yang ◽  
Yin Mi ◽  
...  
Keyword(s):  
Glioma Cell ◽  
High Expression ◽  
Circular Rnas ◽  
Invasion And Migration ◽  
Cellular Processes ◽  
Cell Progression ◽  
And Migration ◽  
Glioma Progression

AbstractCircular RNAs (circRNAs) are a newly identifed non-coding RNA in many cellular processes and tumours. This study aimed to investigate the role of hsa_circ_0037251, one circRNA generated from several exons of the gene termed METRN, in glioma progression. Through in vitro experiments, we discovered that high expression of hsa_circ_0037251 was related to low expression of the microRNA miR-1229-3p and high expression of mTOR. The over-expressed hsa_circ_0037251 promoted cell proliferation, invasion and migration in glioma, while knockdown of hsa_circ_00037251 promoted cell apoptosis and induced G1 phase arrest. Then, hsa_circ_0037251 was observed to directly sponge miR-1229-3p, and mTOR was identified as a direct target of miR-1229-3p. In addition, knockdown of hsa_circ_0037251 up-regulated the expression of miR-1229-3p and inhibited the expression of mTOR. And overexpression of miR-1229-3p or low-expressed mTOR inhibited the glioma cell progression. Furthermore, transfection with mTOR overexpression vectors can restore the abilities of glioma cell progression even if hsa_circ_00037251 was knocked down using siRNAs. In vivo experiments revealed that hsa_circ_00037251 promoted the growth of xenografted tumours and shortened the survival period. These results indicated that hsa_circ_0037251 may act as a tumour promoter by a hsa_circ_0037251/miR-1229-3p/mTOR axis, and these potential biomarkers may be therapeutic targets for glioma.

Adipose tissue, obesity and adipokines: role in cancer promotion

2015 ◽  
Vol 21 (1) ◽  
Author(s):  
Andrea Booth ◽  
Aaron Magnuson ◽  
Josephine Fouts ◽  
Michelle Foster
Keyword(s):  
Adipose Tissue ◽  
Cancer Risk ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epidemiological Studies ◽  
Normal Weight ◽  
Cell Progression ◽  
High Cancer Risk ◽  
Apoptosis Pathways ◽  
And Migration

AbstractAdipose tissue is a complex organ with endocrine, metabolic and immune regulatory roles. Adipose depots have been characterized to release several adipocytokines that work locally in an autocrine and paracrine fashion or peripherally in an endocrine fashion. Adipocyte hypertrophy and excessive adipose tissue accumulation, as occurs during obesity, dysregulates the microenvironment within adipose depots and systemically alters peripheral tissue metabolism. The term “adiposopathy” is used to describe this promotion of pathogenic adipocytes and associated adipose – elated disorders. Numerous epidemiological studies confirm an association between obesity and various cancer forms. Proposed mechanisms that link obesity/adiposity to high cancer risk and mortality include, but are not limited to, obesity-related insulin resistance, hyperinsulinemia, sustained hyperglycemia, glucose intolerance, oxidative stress, inflammation and/or adipocktokine production. Several epidemiological studies have demonstrated a relationship between specific circulating adipocytokines and cancer risk. The aim of this review is to define the function, in normal weight and obesity states, of well-characterized and novel adipokines including leptin, adiponectin, apelin, visfatin, resistin, chemerin, omentin, nesfatin and vaspin and summarize the data that relates their dysfunction, whether associated or direct effects, to specific cancer outcomes. Overall research suggests most adipokines promote cancer cell progression via enhancement of cell proliferation and migration, inflammation and anti-apoptosis pathways, which subsequently can prompt cancer metastasis. Further research and longitudinal studies are needed to define the specific independent and additive roles of adipokines in cancer progression and reoccurrence.

scholarly journals The role of RelA (p65) threonine 505 phosphorylation in the regulation of cell growth, survival, and migration

2011 ◽  
Vol 22 (17) ◽  
pp. 3032-3040 ◽  
Author(s):  
Aichi Msaki ◽  
Ana M. Sánchez ◽  
Li Fang Koh ◽  
Benjamin Barré ◽  
Sonia Rocha ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Cellular Migration ◽  
Negative Regulator ◽  
Drug Induced ◽  
Conserved Residues ◽  
Cellular Processes ◽  
And Migration ◽  
Induced Apoptosis ◽  
Proliferation And Migration

The NF-κB family of transcription factors is a well-established regulator of the immune and inflammatory responses and also plays a key role in other cellular processes, including cell death, proliferation, and migration. Conserved residues in the trans-activation domain of RelA, which can be posttranslationally modified, regulate divergent NF-κB functions in response to different cellular stimuli. Using rela−/−mouse embryonic fibroblasts reconstituted with RelA, we find that mutation of the threonine 505 (T505) phospho site to alanine has wide-ranging effects on NF-κB function. These include previously described effects on chemotherapeutic drug-induced apoptosis, as well as new roles for this modification in autophagy, cell proliferation, and migration. This last effect was associated with alterations in the actin cytoskeleton and expression of cellular migration–associated genes such as WAVE3 and α-actinin 4. We also define a new component of cisplatin-induced, RelA T505–dependent apoptosis, involving induction of NOXA gene expression, an effect explained at least in part through induction of the p53 homologue, p73. Therefore, in contrast to other RelA phosphorylation events, which positively regulate NF-κB function, we identified RelA T505 phosphorylation as a negative regulator of its ability to induce diverse cellular processes such as apoptosis, autophagy, proliferation, and migration.

Postnatal amniotic fluid intake reduces gut inflammatory responses and necrotizing enterocolitis in preterm neonates

2013 ◽  
Vol 304 (10) ◽  
pp. G864-G875 ◽  
Author(s):  
Jayda Siggers ◽  
Mette V. Østergaard ◽  
Richard H. Siggers ◽  
Kerstin Skovgaard ◽  
Lars Mølbak ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
Necrotizing Enterocolitis ◽  
Enteral Feeding ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Preterm Neonates ◽  
Gut Colonization ◽  
Tnf Α ◽  
Before And After ◽  
And Migration

Preterm neonates are susceptible to gastrointestinal disorders such as necrotizing enterocolitis (NEC). Maternal milk and colostrum protects against NEC via growth promoting, immunomodulatory, and antimicrobial factors. The fetal enteral diet amniotic fluid (AF), contains similar components, and we hypothesized that postnatal AF administration reduces inflammatory responses and NEC in preterm neonates. Preterm pigs (92% gestation) were delivered by caesarean section and fed parental nutrition (2 days) followed by enteral (2 days) porcine colostrum (COLOS, n = 7), infant formula (FORM, n = 13), or AF supplied before and after introduction of formula (AF, n = 10) in experiment 1, and supplied only during the enteral feeding period in experiment 2 (FORM, n = 16; AF, n = 14). The NEC score was reduced in both AF and COLOS pigs, relative to FORM, when AF was provided prior to full enteral feeding (9.9 and 7.7 compared with 17.3, P < 0.05). There was no effect of AF when provided only during enteral feeding. AF pigs showed decreased bacterial abundance in colon and intestinal inflammation-related genes (e.g., TNF-α, IL-1α, IL-6, NOS) were downregulated, relative to FORM pigs with NEC. Anti-inflammatory properties of AF were supported by delayed maturation and decreased TNF-α production in murine dendritic cells, as well as increased proliferation and migration, and downregulation of IL-6 expression in intestinal cells (IEC-6, IPEC-J2). Like colostrum, AF may reduce NEC development in preterm neonates by suppressing the proinflammatory responses to enteral formula feeding and gut colonization when provided before the onset of NEC.

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