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https://www.readbyqxmd.com/read/28934273/novel-derivative-of-paeonol-paeononlsilatie-sodium-alleviates-behavioral-damage-and-hippocampal-dendritic-injury-in-alzheimer-s-disease-concurrent-with-cofilin1-phosphorylated-cofilin1-and-rac1-cdc42-alterations-in-rats
#1
Fei Han, Ting-Ting Zhuang, Jing-Jing Chen, Xiu-Ling Zhu, Ya-Fei Cai, Ya-Ping Lu
Alzheimer's disease (AD) is a typical hippocampal amnesia and the most common senile dementia. Many studies suggest that cognitive impairments are more closely correlated with synaptic loss than the burden of amyloid deposits in AD progression. To date, there is no effective treatment for this disease. Paeonol has been widely employed in traditional Chinese medicine. This compound improves learning behavior in an animal model; however, the mechanism remains unclear. In this study, Paeononlsilatie sodium (Pa), a derivative of Paeonol, attenuated D-galactose (D-gal) and AlCl3-induced behavioral damages in rats based on evaluations of the open field test (OFT), elevated plus maze test (EPMT), and Morris water maze test (MWMT)...
2017: PloS One
https://www.readbyqxmd.com/read/28928363/an-autism-spectrum-disorder-related-de-novo-mutation-hotspot-discovered-in-the-gef1-domain-of-trio
#2
Anastasiia Sadybekov, Chen Tian, Cosimo Arnesano, Vsevolod Katritch, Bruce E Herring
The Rho guanine nucleotide exchange factor (RhoGEF) Trio promotes actin polymerization by directly activating the small GTPase Rac1. Recent studies suggest that autism spectrum disorder (ASD)-related behavioral phenotypes in animal models of ASD can be produced by dysregulation of Rac1's control of actin polymerization at glutamatergic synapses. Here, in humans, we discover a large cluster of ASD-related de novo mutations in Trio's Rac1 activating domain, GEF1. Our study reveals that these mutations produce either hypofunctional or hyperfunctional forms of Trio in rodent neurons in vitro...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28927892/cd100-plexin-b2-promotes-the-inflammation-in-psoriasis-by-activating-nf-%C3%AE%C2%BAb-and-inflammasome-in-keratinocytes
#3
Chen Zhang, Chunying Xiao, Erle Dang, Jiao Cao, Zhenlai Zhu, Meng Fu, Xu Yao, Yufeng Liu, Boquan Jin, Gang Wang, Wei Li
Plexin-B2 (PlxnB2) and its ligand, CD100 (Semaphorin 4D), are originally identified as axon-guidance molecules that function during neuronal development; however, studies also showed that CD100-Plexins participate in various immune responses. In the present study, we found that the expression of PlxnB2 on keratinocytes was specifically increased in lesional skin of psoriasis patients, but not atopic dermatitis. Levels of soluble CD100 (sCD100) and membrane CD100 (mCD100) were elevated in sera of psoriasis patients and on keratinocytes of psoriatic skin, respectively...
September 16, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28919558/cellular-uptake-of-extracellular-vesicles-is-mediated-by-clathrin-independent-endocytosis-and-macropinocytosis
#4
Helena Costa Verdera, Jerney J Gitz-Francois, Raymond M Schiffelers, Pieter Vader
Recent evidence has established that extracellular vesicles (EVs), including exosomes and microvesicles, form an endogenous transport system through which biomolecules, including proteins and RNA, are exchanged between cells. This endows EVs with immense potential for drug delivery and regenerative medicine applications. Understanding the biology underlying EV-based intercellular transfer of cargo is of great importance for the development of EV-based therapeutics. Here, we sought to characterize the cellular mechanisms involved in EV uptake...
September 14, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28915620/prpf-overexpression-induces-drug-resistance-through-actin-cytoskeleton-rearrangement-and-epithelial-mesenchymal-transition
#5
Salman Ul Islam, Adeeb Shehzad, Jong Kyung Sonn, Young Sup Lee
Pre-mRNA processing factor (PRPF) 4B kinase belongs to the CDK-like kinase family, and is involved in pre-mRNA splicing, and in signal transduction. In this study, we observed that PRPF overexpression decreased the intracellular levels of reactive oxygen species, and inhibited resveratrol-induced apoptosis by activating the cell survival signaling proteins NFκB, ERK, and c-MYC in HCT116 human colon cancer cells. PRPF overexpression altered cellular morphology, and rearranged the actin cytoskeleton, by regulating the activity of Rho family proteins...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28912177/rac1-functions-downstream-of-mir-142-in-regulation-of-erythropoiesis
#6
Natali Rivkin, Elik Chapnik, Yehudit Birger, Eran Yanowski, Caterina Curato, Alexander Mildner, Ziv Porat, Gail Amir, Shai Izraeli, Steffen Jung, Eran Hornstein
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September 14, 2017: Haematologica
https://www.readbyqxmd.com/read/28912124/kindlin-2-recruits-paxillin-and-arp2-3-to-promote-membrane-protrusions-during-initial-cell-spreading
#7
Ralph T Böttcher, Maik Veelders, Pascaline Rombaut, Jan Faix, Marina Theodosiou, Theresa E Stradal, Klemens Rottner, Roy Zent, Franz Herzog, Reinhard Fässler
Cell spreading requires the coupling of actin-driven membrane protrusion and integrin-mediated adhesion to the extracellular matrix. The integrin-activating adaptor protein kindlin-2 plays a central role for cell adhesion and membrane protrusion by directly binding and recruiting paxillin to nascent adhesions. Here, we report that kindlin-2 has a dual role during initial cell spreading: it binds paxillin via the pleckstrin homology and F0 domains to activate Rac1, and it directly associates with the Arp2/3 complex to induce Rac1-mediated membrane protrusions...
September 14, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28911825/paving-the-rho-in-cancer-metastasis-rho-gtpases-and-beyond
#8
REVIEW
Sepp Jansen, Reinoud Gosens, Thomas Wieland, Martina Schmidt
Malignant carcinomas are often characterized by metastasis, the movement of carcinoma cells from a primary site to colonize distant organs. For metastasis to occur, carcinoma cells first must adopt a pro-migratory phenotype and move through the surrounding stroma towards a blood or lymphatic vessel. Currently, there are very limited possibilities to target these processes therapeutically. The family of Rho GTPases is an ubiquitously expressed division of GTP-binding proteins involved in the regulation of cytoskeletal dynamics and intracellular signaling...
September 11, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28893557/transcription-factor-cux1-is-required-for-intestinal-epithelial-wound-healing-and-targets-the-vav2-rac1-signalling-complex
#9
Roxanne Latreille, Raphaëlle Servant, Mathieu Darsigny, Sébastien Marcoux, Christine Jones, Nathalie Perreault, François Boudreau
Intestinal epithelial cells form a protective barrier in limiting gut luminal content potentially harmful to the host. Upon gut epithelium injury, several signals instruct epithelial cells to undergo a rapid healing process. Defects in this process induce inflammatory responses and can further evolve into chronic gut inflammatory diseases. We previously identified the transcription factor CUX1 as crucial for protecting against experimental colitis in mice. However, the precise molecular mechanisms by which CUX1 intervenes during this biological process are unknown...
September 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28892080/differential-effects-on-lung-and-bone-metastasis-of-breast-cancer-by-wnt-signalling-inhibitor-dkk1
#10
Xueqian Zhuang, Hao Zhang, Xiaoyan Li, Xiaoxun Li, Min Cong, Fangli Peng, Jingyi Yu, Xue Zhang, Qifeng Yang, Guohong Hu
Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non-canonical WNT/PCP-RAC1-JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca(2+)-CaMKII-NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells...
September 11, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28886345/rac1-missense-mutations-in-developmental-disorders-with-diverse-phenotypes
#11
Margot R F Reijnders, Nurhuda M Ansor, Maria Kousi, Wyatt W Yue, Perciliz L Tan, Katie Clarkson, Jill Clayton-Smith, Ken Corning, Julie R Jones, Wayne W K Lam, Grazia M S Mancini, Carlo Marcelis, Shehla Mohammed, Rolph Pfundt, Maian Roifman, Ronald Cohn, David Chitayat, Tom H Millard, Nicholas Katsanis, Han G Brunner, Siddharth Banka
RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p...
September 7, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28882897/the-tiam1-guanine-nucleotide-exchange-factor-is-auto-inhibited-by-its-pleckstrin-homology-coiled-coil-extension-domain
#12
Zhen Xu, Lokesh Gakhar, Fletcher E Bain, Maria Spies, Ernesto J Fuentes
T-cell lymphoma invasion and metastasis 1 (Tiam1) is a Dbl-family guanine nucleotide exchange factor (GEF) that specifically activates the Rho-family GTPase Rac1 in response to upstream signals, thereby regulating cellular processes including cell adhesion and migration. Tiam1 contains multiple domains, including an N-terminal Pleckstrin homology coiled-coiled extension (PHn-CC-Ex) and catalytic Dbl-homology and C-terminal Pleckstrin homology (DH-PHc) domain. Previous studies indicate that larger fragments of Tiam1, such the region encompassing the N-terminal to C-terminal Pleckstrin homology domains (PHn-PHc) are auto-inhibited...
September 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28880939/arf6-mediates-nephrin-tyrosine-phosphorylation-induced-podocyte-cellular-dynamics
#13
Jamie S Lin, Jin Seok Jeon, Qingfeng Fan, Hetty N Wong, Matthew B Palmer, Lawrence B Holzman
ADP-ribosylation factor 6 (ARF6) is a small GTPase necessary for regulating cellular structure, motility, and vesicle trafficking. In several cellular systems, ARF6 was shown to regulate actin dynamics in coordination with Rac1, a Rho small GTPase. We examined the function of ARF6 in the kidney podocyte because Rac1 was implicated in kidney diseases involving this cell. We found that ARF6 expression was enriched in human podocytes and that it modulated podocyte cytoskeletal dynamics through a functional interaction with nephrin, an intercellular junction protein necessary for podocyte injury-induced signaling requiring activation by tyrosine phosphorylation of its cytoplasmic domain...
2017: PloS One
https://www.readbyqxmd.com/read/28880478/role-of-g-proteins-in-islet-function-in-health-and-diabetes
#14
REVIEW
Anjaneyulu Kowluru
Glucose-stimulated insulin secretion (GSIS) involves interplay between metabolic and cationic events. Seminal contributions from multiple laboratories affirm essential roles for small G-proteins (Rac1, Cdc42, Arf6, Rab27A) in GSIS. Activation of these signalling proteins promotes cytoskeletal remodeling, transport and docking of insulin granules on the plasma membrane for exocytotic secretion of insulin. Evidence in rodent and human islets suggests key roles for lipidation (farnesylation and geranylgeranylation) of these G-proteins for their targeting to appropriate cellular compartments for optimal regulation of effectors leading to GSIS...
September 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28874564/endodermal-germ-layer-formation-through-active-actin-driven-migration-triggered-by-n-cadherin
#15
Florence A Giger, Nicolas B David
Germ-layer formation during gastrulation is both a fundamental step of development and a paradigm for tissue formation and remodeling. However, the cellular and molecular basis of germ-layer segregation is poorly understood, mostly because of the lack of direct in vivo observations. We used mosaic zebrafish embryos to investigate the formation of the endoderm. High-resolution live imaging and functional analyses revealed that endodermal cells reach their characteristic innermost position through an active, oriented, and actin-based migration dependent on Rac1, which contrasts with the previously proposed differential adhesion cell sorting...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28874189/intersectin-1s-deficiency-in-pulmonary-pathogenesis
#16
REVIEW
Niranjan Jeganathan, Dan Predescu, Sanda Predescu
Intersectin-1s (ITSN-1s), a multidomain adaptor protein, plays a vital role in endocytosis, cytoskeleton rearrangement and cell signaling. Recent studies have demonstrated that deficiency of ITSN-1s is a crucial early event in pulmonary pathogenesis. In lung cancer, ITSN-1s deficiency impairs Eps8 ubiquitination and favors Eps8-mSos1 interaction which activates Rac1 leading to enhanced lung cancer cell proliferation, migration and metastasis. Restoring ITSN-1s deficiency in lung cancer cells facilitates cytoskeleton changes favoring mesenchymal to epithelial transformation and impairs lung cancer progression...
September 6, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28869598/rcc2-is-a-novel-p53-target-in-suppressing-metastasis
#17
C Song, L Liang, Y Jin, Y Li, Y Liu, L Guo, C Wu, C-H Yun, Y Yin
RCC2 (also known as TD60) is a highly conserved protein involved in prognosis in colorectal cancer. However, its relationship with tumor development is less understood. Here we demonstrate a signaling pathway defining regulation of RCC2 and its functions in tumor progression. We report that p53 is a transcriptional regulator of RCC2 that acts through its binding to a palindromic motif in the RCC2 promoter. RCC2 physically interacts and deactivates a small GTPase Rac1 that is known to be involved in metastasis...
September 4, 2017: Oncogene
https://www.readbyqxmd.com/read/28865956/developmentally-regulated-gtp-binding-protein-2-is-required-for-stabilization-of-rac1-positive-membrane-tubules
#18
Muralidharan Mani, Unn Hwa Lee, Nal Ae Yoon, Eun Hye Yoon, Byung Ju Lee, Wha Ja Cho, Jeong Woo Park
Previously we have reported that developmentally regulated GTP-binding protein 2 (DRG2) localizes on Rab5 endosomes and plays an important role in transferrin (Tfn) recycling. We here identified DRG2 as a key regulator of membrane tubule stability. At 30 min after Tfn treatment, DRG2 localized to membrane tubules which were enriched with phosphatidylinositol 4-monophosphate [PI(4)P] and did not contain Rab5. DRG2 interacted with Rac1 more strongly with GTP-bound Rac1 and tubular localization of DRG2 depended on Rac1 activity...
September 1, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28860633/a-cdc42-centered-signaling-unit-is-a-dominant-positive-regulator-of-endothelial-integrity
#19
J Amado-Azevedo, N R Reinhard, J van Bezu, R X de Menezes, V W van Beusechem, G P van Nieuw Amerongen, V W M van Hinsbergh, P L Hordijk
Endothelial barrier function is carefully controlled to protect tissues from edema and damage inflicted by extravasated leukocytes. RhoGTPases, in conjunction with myriad regulatory proteins, exert both positive and negative effects on the endothelial barrier integrity. Precise knowledge about the relevant mechanisms is currently fragmented and we therefore performed a comprehensive analysis of endothelial barrier regulation by RhoGTPases and their regulators. Combining RNAi with electrical impedance measurements we quantified the relevance of 270 Rho-associated genes for endothelial barrier function...
August 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28855187/inhibition-of-smooth-muscle-contraction-and-arf-6-activity-by-the-inhibitor-for-cytohesin-gefs-secinh3-in-the-human-prostate
#20
Annika Herlemann, Patrick Keller, Melanie Schott, Alexander Tamalunas, Anna Ciotkowska, Beata Rutz, Yiming Wang, Qingfeng Yu, Raphaela Waidelich, Frank Strittmatter, Christian G Stief, Christian Gratzke, Martin Hennenberg
Prostate smooth muscle contraction is critical for etiology and treatment of male lower urinary tract symptoms (LUTS), and is promoted by small monomeric GTPases (RhoA, Rac). GTPases may be activated by guanosine nucleotide exchange factors (GEFs). GEFs of the cytohesin family may indirectly activate Rac, or ADP ribosolyation factor (ARF) GTPases directly. Here we investigated the expression of cytohesin family GEFs, and effects of the cytohesin inhibitor secinH3 on smooth muscle contraction and GTPase activities in human prostate tissues...
August 30, 2017: American Journal of Physiology. Renal Physiology
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