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Irene Maffucci, Xiao Hu, Valentina Fumagalli, Alessandro Contini
Nwat-MMGBSA is a variant of MM-PB/GBSA based on the inclusion of a number of explicit water molecules that are the closest to the ligand in each frame of a molecular dynamics trajectory. This method demonstrated improved correlations between calculated and experimental binding energies in both protein-protein interactions and ligand-receptor complexes, in comparison to the standard MM-GBSA. A protocol optimization, aimed to maximize efficacy and efficiency, is discussed here considering penicillopepsin, HIV1-protease, and BCL-XL as test cases...
2018: Frontiers in Chemistry
Sandra G Gonzalez Malagon, Anna M Lopez Muñoz, Daniel Doro, Triòna G Bolger, Evon Poon, Elizabeth R Tucker, Hadeel Adel Al-Lami, Matthias Krause, Christopher J Phiel, Louis Chesler, Karen J Liu
Neural crest migration is critical to its physiological function. Mechanisms controlling mammalian neural crest migration are comparatively unknown, due to difficulties accessing this cell population in vivo. Here we report requirements of glycogen synthase kinase 3 (GSK3) in regulating the neural crest in Xenopus and mouse models. We demonstrate that GSK3 is tyrosine phosphorylated (pY) in mouse neural crest cells and that loss of GSK3 leads to increased pFAK and misregulation of Rac1 and lamellipodin, key regulators of cell migration...
March 19, 2018: Nature Communications
Pingping Xia, Yundan Pan, Fan Zhang, Na Wang, E Wang, Qulian Guo, Zhi Ye
BACKGROUND/AIMS: Recent researches highlighted the protective potential of pioglitazone, a PPAR-γ agonist, in the progression of cerebral ischemia-reperfusion injury. However, there has been no study on the application of pioglitazone in treating ischemic stroke through mechanisms involving pyroptosis. METHODS: The cerebral injury was established by middle cerebral artery occlusion (MCAO). in vitro ischemia in primary cultured astrocytes was induced by the oxygen-glucose deprivation (OGD)...
March 13, 2018: Cellular Physiology and Biochemistry
Xuchen Zhang, Qian Li, Lianzhang Wang, Zhong-Jian Liu, Yi Zhong
Active forgetting explains the intrinsic instability of a labile memory lasting for hours. However, how such memory maintains stability against unwanted disruption is not completely understood. Here, we report a learning-activated active protection mechanism that enables labile memory to resist disruptive sensory experiences in Drosophila. Aversive olfactory conditioning activates mitogen-activated protein kinase (MAPK) transiently in the mushroom-body γ lobe, where labile-aversive memory is stored. This increased MAPK activity significantly prolongs labile memory retention and enhances its resistance to disruption induced by heat shock, electric shock, or odor reactivation...
March 7, 2018: Neuron
G A Cardama, D F Alonso, N Gonzalez, J Maggio, D E Gomez, C Rolfo, P L Menna
Rac1 GTPase signaling pathway has a critical role in the regulation of a plethora of cellular functions governing cancer cell behavior. Recently, it has been shown a critical role of Rac1 in the emergence of resistance mechanisms to cancer therapy. This review describes the current knowledge regarding Rac1 pathway deregulation and its association with chemoresistance, radioresistance, resistance to targeted therapies and immune evasion. This supports the idea that interfering Rac1 signaling pathway could be an interesting approach to tackle cancer resistance...
April 2018: Critical Reviews in Oncology/hematology
Ali Ben Djoudi Ouadda, Yi He, Viviane Calabrese, Hidetaka Ishii, Rony Chidiac, Jean-Philippe Gratton, Philippe P Roux, Nathalie Lamarche-Vane
Cdc42 GTPase-activating protein (CdGAP, also named ARHGAP31) is a negative regulator of the GTPases Rac1 and Cdc42. Associated with the rare developmental disorder Adams-Oliver Syndrome (AOS), CdGAP is critical for embryonic vascular development and VEGF-mediated angiogenesis. Moreover, CdGAP is an essential component in the synergistic interaction between TGFβ and ErbB-2 signaling pathways during breast cancer cell migration and invasion, and is a novel E-cadherin transcriptional co-repressor with Zeb2 in breast cancer...
February 20, 2018: Oncotarget
Ines Marek, Robert Becker, Fabian B Fahlbusch, Carlos Menendez-Castro, Wolfgang Rascher, Christoph Daniel, Gudrun Volkert, Andrea Hartner
BACKGROUND/AIMS: Healing of mesangioproliferative glomerulonephritis involves degradation of excess extracellular matrix, resolution of hypercellularity by apoptosis and phagocytosis of apoptotic cells. Integrin receptors participate in the regulation of phagocytosis. In mice deficient for alpha8 integrin (Itga8-/-) healing of glomerulonephritis is delayed. As Itga8 is abundant in mesangial cells (MC) which are non-professional phagocytes, we hypothesized that Itga8 facilitates phagocytosis of apoptotic cells and matrix components by MC...
March 10, 2018: Cellular Physiology and Biochemistry
Teklab Gebregiworgis, Christopher Boyd Marshall, Tadateru Nishikawa, Nikolina Radulovich, María-José Sandi, Zhenhao Fang, Robert Rottapel, Ming-Sound Tsao, Mitsuhiko Ikura
Small GTPases (sGTPases) are critical switch-like regulators that mediate several important cellular functions and are often mutated in human cancers. They are activated by guanine nucleotide exchange factors (GEFs), which specifically catalyze the exchange of GTP for GDP. GEFs coordinate signaling networks in normal cells, and are frequently deregulated in cancers. sGTPase signaling pathways are complex and interconnected; however, most GEF assays do not reveal such complexity. In this communication, we describe the development of a unique real-time NMR-based multiplexed GEF assay that employs distinct isotopic labeling schemes for each sGTPase protein to enable simultaneous observation of six proteins of interest...
March 15, 2018: Journal of the American Chemical Society
Alexis Bonfim-Melo, Éden R Ferreira, Renato A Mortara
This study evaluated the participation of host cell Rho-family GTPases and their effector proteins in the actin-dependent invasion by Trypanosoma cruzi extracellular amastigotes (EAs). We observed that all proteins were recruited and colocalized with actin at EA invasion sites in live or fixed cells. EA internalization was inhibited in cells depleted in Rac1, N-WASP, and WAVE2. Time-lapse experiments with Rac1, N-WASP and WAVE2 depleted cells revealed that EA internalization kinetics is delayed even though no differences were observed in the proportion of EA-induced actin recruitment in these groups...
2018: Frontiers in Microbiology
Ryo Hatano, Ai Takeda, Yukiko Abe, Kotoku Kawaguchi, Itsuro Kazama, Mitsunobu Matsubara, Shinji Asano
Ezrin is highly expressed in glomerular podocytes and is reported to form a multi-protein complex with scaffold protein Na+ /H+ exchanger regulatory factor 2 (NHERF2) and podocalyxin, a major sialoprotein. Podocalyxin-knockout mice died within 24 h of birth with anuric renal failure, whereas NHERF2-knockout mice show no apparent changes in the glomerular functions. However, the physiological roles of ezrin in glomerular podocytes remain unclear. Here, we investigated the importance of ezrin in the regulation of glomerular podocyte function using ezrin-knockdown mice (Vil2kd/kd )...
March 14, 2018: Scientific Reports
Jinhua Dai, Jianbo Ma, Bixia Yu, Zhankun Zhu, Yanqin Hu
Glioma is the most common primary adult brain tumor. Mounting researches have illustrated the function of long non-coding RNAs (lncRNAs) in glioma progress, but almost no studies reported the role of TCL1 Upstream Neural Differentiation-Associated RNA (TUNAR) in glioma cells. This study aimed to investigate the function of TUNAR in glioma. GL15 cell line was used in this study. The interactions between TUNAR and miR-200a, or miR-200a and Rac1 were determined by co-transfection experiment. TUNAR overexpression significantly inhibited glioma malignancy by decreasing cell viability, migration, invasion and promoting cell apoptosis...
March 14, 2018: Oncology Research
Richard T Amison, Shirin Jamshidi, Khondaker M Rahman, Clive P Page, Simon C Pitchford
Platelet P2Y1 receptor signaling via RhoGTPases is necessary for platelet-dependent leukocyte recruitment, where no platelet aggregation is observed. We investigated signaling cascades involved in distinct P2Y1 -dependent platelet activities in vitro, using specific inhibitors for phospholipase C (PLC) (U73122, to inhibit the canonical pathway), and RhoGTPases: Rac1 (NSC23766) and RhoA (ROCK inhibitor GSK429286). Human platelet rich plasma (for platelet aggregation) or isolated washed platelets (for chemotaxis assays) was treated with U73122, GSK429286 or NSC23766 prior to stimulation with adenosine diphosphate (ADP) or the P2Y1 specific agonist MRS2365...
March 10, 2018: European Journal of Pharmacology
Kiyoshi Takagi, Yasuhiro Miki, Yoshiaki Onodera, Takanori Ishida, Mika Watanabe, Hironobu Sasano, Takashi Suzuki
Rho GTPase activating protein 15 (ARHGAP15) is a recently identified GTPase activating protein which enhances intrinsic hydrolysis of GTP-bound Ras-related C3 botulinus toxin substrate (Rac1), resulting in inactivation of Rac1. Although a lot of studies have pointed out the pivotal roles of the Rac1 pathway in the progression of breast carcinomas, the clinical significance of ARHGAP15 has remained largely unknown in human breast carcinomas. Therefore, we immunolocalized ARHGAP15 in one hundred breast carcinoma tissues...
March 10, 2018: International Journal of Molecular Sciences
Sawana Singkhorn, Mayuree H Tantisira, Supita Tanasawet, Pilaiwanwadee Hutamekalin, Tulaporn Wongtawatchai, Wanida Sukketsiri
Centella asiatica is widely considered the most important medicinal plant for treating and relieving skin diseases. Recently developed standardized extract of Centella asiatica ECa 233 has demonstrated positive effects on wound healing of incision and burn wound in rats. However, knowledge associated with wound healing mechanism of ECa 233 was scare. Therefore, this study aimed to investigate the effect and underlying molecular mechanisms of ECa 233 on the migration of a human keratinocyte cell line (HaCaT) using scratch wound healing assay...
March 13, 2018: Phytotherapy Research: PTR
Manon Viaud, Stoyan Ivanov, Nemanja Vujic, Madalina Duta-Mare, Lazaro-Emilio Aira, Thibault Barouillet, Elsa Garcia, François Orange, Isabelle Dugail, Isabelle Hainault, Christian Stehlik, Sandrine Marchetti, Laurent Boyer, Rodolphe Guinamard, Fabienne Foufelle, Andrea E Bochem, Kees G Hovingh, Edward B Thorp, Emmanuel L Gautier, Dagmar Kratky, Paul A Da Silva-Jardine, Laurent Yvan-Charvet
<u>Rationale:</u> Macrophages face a substantial amount of cholesterol following the ingestion of apoptotic cells and the lysosomal acid lipase (LIPA) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment. <u>Objective:</u> Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. <u>Methods and Results:</u> We show that LIPA inhibition causes a defective efferocytic response due to impaired generation of 25-OHC and 27-OHC...
March 9, 2018: Circulation Research
Sofia Golenkina, Vishal Chaturvedi, Robert Saint, Michael J Murray
Netrin receptors of the DCC/NEO/UNC-40/Frazzled family have well established roles in cell migration and axon guidance but can also regulate epithelial features such as adhesion, polarity and adherens junction (AJ) stability. Previously, we have shown that overexpression of Drosophila Frazzled (Fra) in the peripodial epithelium (PE) inhibits wing disc eversion and also generates cellular protrusions typical of motile cells. Here, we tested whether the molecular pathways by which Fra inhibits eversion are distinct from those driving motility...
2018: PloS One
Fenghua Chen, Jibrin Danladi, Maryam Ardalan, Betina Elfving, Heidi K Müller, Gregers Wegener, Connie Sanchez, Jens R Nyengaard
Background: Preclinical studies have indicated that antidepressant effect of vortioxetine involves increased synaptic plasticity and promotion of spine maturation. Mitochondria dysfunction may contribute to the pathophysiological basis of major depressive disorder. Taking into consideration that vortioxetine increases spine number and dendritic branching in hippocampus CA1 faster than fluoxetine, we hypothesize that new spines induced by vortioxetine can rapidly form functional synapses by mitochondrial support, accompanied by increased brain-derived neurotrophic factor (BDNF)-signaling...
March 5, 2018: International Journal of Neuropsychopharmacology
Ji Pang, Pengcheng Jiang, Ying Wang, Lu Jiang, Hai Qian, Yan Tao, Ruxia Shi, Jizong Gao, Yongchang Chen, Yan Wu
BACKGROUND: The recurrence, metastasis and poor prognosis are important characteristics of ovarian carcinoma (OC), which are associated with exfoliation of cells from the primary tumor and colonization of the cells in pelvic cavity. On the other hand, the life quality of the patients undergoing surgical resection of OC was influenced by postoperative adhesions. Therefore, preventing postoperative implant tumor and adhesion may be effective methods to improve OC treatment. HyaRegen Gel, a cross-linked hyaluronan gel (CHAG), has been widely used as an anti-adhesive agent following pelvic operation in clinic...
March 6, 2018: Journal of Ovarian Research
Virginia Tajadura-Ortega, Ritu Garg, Richard Allen, Claudia Owczarek, Michael D Bright, Samuel Kean, Aisyah Mohd-Noor, Anita Grigoriadis, Timothy C Elston, Klaus M Hahn, Anne J Ridley
BACKGROUND: Cell migration is essential for development and tissue repair, but it also contributes to disease. Rho GTPases regulate cell migration, but a comprehensive analysis of how each Rho signalling component affects migration has not been carried out. RESULTS: Through an RNA interference screen, and using a prostate cancer cell line, we find that approximately 25% of Rho network components alter migration. Some genes enhance migration while others decrease basal and/or hepatocyte growth factor-stimulated migration...
March 6, 2018: BMC Biology
Chien-Huang Lin, Chung-Huang Shih, Yu-Chang Lin, You-Lan Yang, Bing-Chang Chen
BACKGROUND: In idiopathic pulmonary fibrosis, the interaction of CXCL12 and CXC receptor 4 (CXCR4) plays a critical role in lung fibrosis. Connective tissue growth factor (CTGF) overexpression underlies the development of pulmonary fibrosis. Our previous report showed that the Rac1-dependent extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and activator protein (AP)-1 pathways are involved in CXCL12-generated CTGF expression in human lung fibroblasts (WI-38)...
March 2, 2018: Journal of Biomedical Science
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