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[PMID]:28700225
[Au] Autor:Skovbakke SL; Holdfeldt A; Nielsen C; Hansen AM; Perez-Gassol I; Dahlgren C; Forsman H; Franzyk H
[Ad] Endereço:Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Jagtvej 162, 2100 Copenhagen East, Denmark.
[Ti] Título:Combining Elements from Two Antagonists of Formyl Peptide Receptor 2 Generates More Potent Peptidomimetic Antagonists.
[So] Source:J Med Chem;60(16):6991-6997, 2017 Aug 24.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Structural optimization of a peptidomimetic antagonist of formyl peptide receptor 2 (FPR2) was explored by an approach involving combination of elements from the two most potent FPR2 antagonists described: a Rhodamine B-conjugated 10-residue gelsonin-derived peptide (i.e., PBP , RhB-QRLFQVKGRR-OH) and the palmitoylated α-peptide/ß-peptoid hybrid Pam-(Lys-ßNspe) -NH . This generated an array of hybrid compounds from which a new subclass of receptor-selective antagonists was identified. The most potent representatives displayed activity in the low nanomolar range. The resulting stable and potent FPR2-selective antagonists (i.e., RhB-(Lys-ßNphe) -NH ; n = 4-6) are expected to become valuable tools in further elucidation of the physiological role of FPR2 in health and disease.
[Mh] Termos MeSH primário: Gelsolina/farmacologia
Fragmentos de Peptídeos/farmacologia
Peptídeos/farmacologia
Peptidomiméticos/farmacologia
Receptores de Formil Peptídeo/antagonistas & inibidores
Receptores de Lipoxinas/antagonistas & inibidores
[Mh] Termos MeSH secundário: Ativadores de Enzimas/farmacologia
Gelsolina/síntese química
Seres Humanos
Estrutura Molecular
N-Formilmetionina Leucil-Fenilalanina/farmacologia
NADPH Oxidases/metabolismo
Neutrófilos/metabolismo
Oligopeptídeos/farmacologia
Fragmentos de Peptídeos/síntese química
Peptídeos/síntese química
Peptídeos/química
Peptidomiméticos/síntese química
Peptidomiméticos/química
Transdução de Sinais/efeitos dos fármacos
Relação Estrutura-Atividade
Superóxidos/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Activators); 0 (FPR2 protein, human); 0 (Gelsolin); 0 (Oligopeptides); 0 (Pam-(Lys-beta-Nspe)6-NH2); 0 (Peptide Fragments); 0 (Peptides); 0 (Peptidomimetics); 0 (Receptors, Formyl Peptide); 0 (Receptors, Lipoxin); 0 (Trp-Lys-Tyr-Met-Val-Met); 0 (gelsolin (160-169)); 11062-77-4 (Superoxides); 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine); EC 1.6.3.- (NADPH Oxidases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00489


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[PMID]:28695858
[Au] Autor:Panneerselvam S; Kumpula EP; Kursula I; Burkhardt A; Meents A
[Ad] Endereço:Photon Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany.
[Ti] Título:Rapid cadmium SAD phasing at the standard wavelength (1 Å).
[So] Source:Acta Crystallogr D Struct Biol;73(Pt 7):581-590, 2017 Jul 01.
[Is] ISSN:2059-7983
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cadmium ions can be effectively used to promote crystal growth and for experimental phasing. Here, the use of cadmium ions as a suitable anomalous scatterer at the standard wavelength of 1 Šis demonstrated. The structures of three different proteins were determined using cadmium single-wavelength anomalous dispersion (SAD) phasing. Owing to the strong anomalous signal, the structure of lysozyme could be automatically phased and built using a very low anomalous multiplicity (1.1) and low-completeness (77%) data set. Additionally, it is shown that cadmium ions can easily substitute divalent ions in ATP-divalent cation complexes. This property could be generally applied for phasing experiments of a wide range of nucleotide-binding proteins. Improvements in crystal growth and quality, good anomalous signal at standard wavelengths (i.e. no need to change photon energy) and rapid phasing and refinement using a single data set are benefits that should allow cadmium ions to be widely used for experimental phasing.
[Mh] Termos MeSH primário: Cádmio/química
Cristalografia por Raios X/métodos
Proteínas/química
[Mh] Termos MeSH secundário: Actinas/química
Actinas/metabolismo
Animais
Sítios de Ligação
Cádmio/metabolismo
Galinhas
Cristalização/métodos
Gelsolina/química
Gelsolina/metabolismo
Modelos Moleculares
Muramidase/química
Muramidase/metabolismo
Plasmodium falciparum/química
Plasmodium falciparum/metabolismo
Conformação Proteica
Proteínas/metabolismo
Proteínas de Protozoários/química
Proteínas de Protozoários/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Gelsolin); 0 (Proteins); 0 (Protozoan Proteins); 00BH33GNGH (Cadmium); EC 3.2.1.17 (Muramidase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.1107/S2059798317006970


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[PMID]:28400331
[Au] Autor:Thiruketheeswaran P; Thomalla P; Krüger E; Hinssen H; D'Haese J
[Ad] Endereço:Institute for Cell Biology, Department Biology, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
[Ti] Título:Four paralog gelsolin genes are differentially expressed in the earthworm Lumbricus terrestris.
[So] Source:Comp Biochem Physiol B Biochem Mol Biol;208-209:58-67, 2017 Jun.
[Is] ISSN:1879-1107
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We have identified and characterized four distinct variants of the gelsolin-related protein (EWAM P1-P4) in the earthworm L. terrestris. All of these proteins biochemically qualify as gelsolins since they sever actin filaments in a calcium dependent manner. P1, P2 and P3 are present in the Lumbricus body wall muscle whereas in the gizzard muscle P3 and P4 were found. P1-P4 are encoded by four paralog genes and are differentially expressed in various muscle cell tissues. While the genes for P1 and P2 contain one intron, there was no intron in both P3 and P4 genes. The coding sequences consist of 1104bp (368 amino acids) for P1/P4 and 1101bp (367 amino acids) for P2/P3. Corresponding genes were confirmed by northern blot analysis which revealed three (calculated lengths: 3100, 2300 and 2100 nucleotides) and two (calculated lengths: 2300 and 1700 nucleotides) mRNA transcripts in the body wall and the gizzard, respectively. EWAM mRNA was localized by fluorescence in situ hybridization in the body wall and the gizzard muscle. P1 mRNA was detected in the inner proximal layers of both the circular and longitudinal muscle of the body wall whereas in the gizzard no significant staining was observed for P1. P2-P4 mRNAs were abundant in the outer distal layers of both the circular and the longitudinal muscles of both body wall and gizzard. The differential expression of four paralog gelsolin genes suggests a functional adaptation of different muscle cells with respect to actin filament turnover and modulation of its polymer state.
[Mh] Termos MeSH primário: Éxons/genética
Gelsolina/genética
Íntrons/genética
Músculos/metabolismo
Oligoquetos/genética
[Mh] Termos MeSH secundário: Animais
Northern Blotting
Gelsolina/classificação
Hibridização in Situ Fluorescente
Oligoquetos/crescimento & desenvolvimento
RNA Mensageiro/genética
Reação em Cadeia da Polimerase em Tempo Real
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gelsolin); 0 (RNA, Messenger)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170413
[St] Status:MEDLINE


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[PMID]:28394337
[Au] Autor:Harterink M; da Silva ME; Will L; Turan J; Ibrahim A; Lang AE; van Battum EY; Pasterkamp RJ; Kapitein LC; Kudryashov D; Barres BA; Hoogenraad CC; Zuchero JB
[Ad] Endereço:Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
[Ti] Título:DeActs: genetically encoded tools for perturbing the actin cytoskeleton in single cells.
[So] Source:Nat Methods;14(5):479-482, 2017 May.
[Is] ISSN:1548-7105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The actin cytoskeleton is essential for many fundamental biological processes, but tools for directly manipulating actin dynamics are limited to cell-permeable drugs that preclude single-cell perturbations. Here we describe DeActs, genetically encoded actin-modifying polypeptides, which effectively induce actin disassembly in eukaryotic cells. We demonstrate that DeActs are universal tools for studying the actin cytoskeleton in single cells in culture, tissues, and multicellular organisms including various neurodevelopmental model systems.
[Mh] Termos MeSH primário: ADP Ribose Transferases/genética
Citoesqueleto de Actina/metabolismo
Actinas/metabolismo
Gelsolina/genética
Peptídeos/genética
Proteínas Recombinantes de Fusão/genética
Fatores de Virulência/genética
[Mh] Termos MeSH secundário: Citoesqueleto de Actina/genética
Actinas/genética
Animais
Fibroblastos/metabolismo
Fibroblastos/ultraestrutura
Proteínas de Fluorescência Verde/genética
Células HeLa
Seres Humanos
Ratos
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Gelsolin); 0 (Peptides); 0 (Recombinant Fusion Proteins); 0 (Virulence Factors); 147336-22-9 (Green Fluorescent Proteins); EC 2.4.2.- (ADP Ribose Transferases); EC 2.4.2.- (spvB protein, Salmonella enterica virulence plasmid)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170411
[St] Status:MEDLINE
[do] DOI:10.1038/nmeth.4257


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[PMID]:28385809
[Au] Autor:Ordija CM; Chiou TT; Yang Z; Deloid GM; de Oliveira Valdo M; Wang Z; Bedugnis A; Noah TL; Jones S; Koziel H; Kobzik L
[Ad] Endereço:Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
[Ti] Título:Free actin impairs macrophage bacterial defenses via scavenger receptor MARCO interaction with reversal by plasma gelsolin.
[So] Source:Am J Physiol Lung Cell Mol Physiol;312(6):L1018-L1028, 2017 Jun 01.
[Is] ISSN:1522-1504
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lung injury can release intracellular actin into the alveolar milieu and is also associated with increased susceptibility to secondary infections. We investigated the effect of free (extracellular) actin on lung macrophage host defense functions. Western blot analysis demonstrated free actin release into the lung lavage fluids of mouse models of ozone injury, influenza infection, and secondary pneumococcal pneumonia and in samples from patients following burn and inhalation injury. Using levels comparable with those observed in lung injury, we found that free actin markedly inhibited murine lung macrophage binding and uptake in vitro of , , and , (e.g., , mean %inhibition, actin vs. vehicle: 85 ± 0.3 (SD); = 22, < .001). Similar effects were observed on the ability of primary human macrophages to bind and ingest fluorescent (~75% inhibition). Plasma gelsolin (pGSN), a protein that functions to bind and cleave actin, restored bacterial binding and uptake by both murine and human macrophages. Scavenger receptor inhibitors reduced binding of fluorescent actin by murine macrophages [fluorescence index (×10 ) after incubation with vehicle, actin, or actin + polyinosinic acid, respectively: 0.8 ± 0.7, 101.7 ± 50.7, or 52.7 ± 16.9; = 5-6, < 0.05]. In addition, actin binding was reduced in a MARCO/SR-AI/II-deficient cell line and by normal AMs obtained from MARCO mice. After release from injured cells during lung injury, free actin likely contributes to impaired host defense by blocking scavenger receptor binding of bacteria. This mechanism for increased risk of secondary infections after lung injury or inflammation may represent another target for therapeutic intervention with pGSN.
[Mh] Termos MeSH primário: Actinas/metabolismo
Gelsolina/sangue
Macrófagos Alveolares/imunologia
Macrófagos Alveolares/microbiologia
Receptores Imunológicos/metabolismo
Receptores Depuradores/metabolismo
[Mh] Termos MeSH secundário: Animais
Bactérias/imunologia
Feminino
Seres Humanos
Lesão Pulmonar/metabolismo
Lesão Pulmonar/patologia
Macrófagos Alveolares/metabolismo
Macrófagos Alveolares/patologia
Masculino
Camundongos Endogâmicos C57BL
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Gelsolin); 0 (Marco protein, mouse); 0 (Receptors, Immunologic); 0 (Receptors, Scavenger)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170408
[St] Status:MEDLINE
[do] DOI:10.1152/ajplung.00067.2017


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[PMID]:28334940
[Au] Autor:Verhelle A; Nair N; Everaert I; Van Overbeke W; Supply L; Zwaenepoel O; Peleman C; Van Dorpe J; Lahoutte T; Devoogdt N; Derave W; Chuah MK; Vanden Driessche T; Gettemans J
[Ad] Endereço:Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
[Ti] Título:AAV9 delivered bispecific nanobody attenuates amyloid burden in the gelsolin amyloidosis mouse model.
[So] Source:Hum Mol Genet;26(7):1353-1364, 2017 Apr 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Gelsolin amyloidosis is a dominantly inherited, incurable type of amyloidosis. A single point mutation in the gelsolin gene (G654A is most common) results in the loss of a Ca2+ binding site in the second gelsolin domain. Consequently, this domain partly unfolds and exposes an otherwise buried furin cleavage site at the surface. During secretion of mutant plasma gelsolin consecutive cleavage by furin and MT1-MMP results in the production of 8 and 5 kDa amyloidogenic peptides. Nanobodies that are able to (partly) inhibit furin or MT1-MMP proteolysis have previously been reported. In this study, the nanobodies have been combined into a single bispecific format able to simultaneously shield mutant plasma gelsolin from intracellular furin and extracellular MT1-MMP activity. We report the successful in vivo expression of this bispecific nanobody following adeno-associated virus serotype 9 gene therapy in gelsolin amyloidosis mice. Using SPECT/CT and immunohistochemistry, a reduction in gelsolin amyloid burden was detected which translated into improved muscle contractile properties. We conclude that a nanobody-based gene therapy using adeno-associated viruses shows great potential as a novel strategy in gelsolin amyloidosis and potentially other amyloid diseases.
[Mh] Termos MeSH primário: Amiloidose/genética
Amiloidose/terapia
Gelsolina/genética
Terapia Genética
[Mh] Termos MeSH secundário: Amiloidose/patologia
Animais
Anticorpos Biespecíficos/imunologia
Anticorpos Biespecíficos/uso terapêutico
Dependovirus/genética
Dependovirus/imunologia
Modelos Animais de Doenças
Furina/imunologia
Furina/uso terapêutico
Gelsolina/imunologia
Seres Humanos
Metaloproteinase 14 da Matriz/imunologia
Metaloproteinase 14 da Matriz/uso terapêutico
Camundongos
Mutação Puntual/genética
Anticorpos de Domínio Único/administração & dosagem
Anticorpos de Domínio Único/genética
Anticorpos de Domínio Único/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Bispecific); 0 (Gelsolin); 0 (Single-Domain Antibodies); EC 3.4.21.75 (Furin); EC 3.4.24.80 (Matrix Metalloproteinase 14)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170515
[Lr] Data última revisão:
170515
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx056


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[PMID]:28280241
[Au] Autor:Singaravelu P; Lee WL; Wee S; Ghoshdastider U; Ding K; Gunaratne J; Grimes JM; Swaminathan K; Robinson RC
[Ad] Endereço:From the Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore 138673.
[Ti] Título: effector protein (YopO)-mediated phosphorylation of host gelsolin causes calcium-independent activation leading to disruption of actin dynamics.
[So] Source:J Biol Chem;292(19):8092-8100, 2017 May 12.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pathogenic bacteria cause a range of human diseases. To modulate and evade host immune systems, these yersiniae inject effector proteins into host macrophages. One such protein, the serine/threonine kinase YopO (YpkA in ), uses monomeric actin as bait to recruit and phosphorylate host actin polymerization-regulating proteins, including the actin-severing protein gelsolin, to disrupt actin filaments and thus impair phagocytosis. However, the YopO phosphorylation sites on gelsolin and the consequences of YopO-mediated phosphorylation on actin remodeling have yet to be established. Here we determined the effects of YopO-mediated phosphorylation on gelsolin and identified its phosphorylation sites by mass spectrometry. YopO phosphorylated gelsolin in the linker region between gelsolin homology domains G3 and G4, which, in the absence of calcium, are compacted but adopt an open conformation in the presence of calcium, enabling actin binding and severing. Using phosphomimetic and phosphodeletion gelsolin mutants, we found that YopO-mediated phosphorylation partially mimics calcium-dependent activation of gelsolin, potentially contributing to a reduction in filamentous actin and altered actin dynamics in phagocytic cells. In summary, this work represents the first report of the functional outcome of serine/threonine phosphorylation in gelsolin regulation and provides critical insight into how YopO disrupts normal gelsolin function to alter host actin dynamics and thus cripple phagocytosis.
[Mh] Termos MeSH primário: Actinas/química
Proteínas de Bactérias/metabolismo
Cálcio/química
Gelsolina/química
Proteínas Serina-Treonina Quinases/metabolismo
Yersinia/metabolismo
[Mh] Termos MeSH secundário: Citoesqueleto de Actina/metabolismo
Sítios de Ligação
Seres Humanos
Macrófagos/microbiologia
Espectrometria de Massas
Simulação de Dinâmica Molecular
Mutação
Fagocitose
Fosforilação
Domínios Proteicos
Pirenos/química
Serina/química
Treonina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Bacterial Proteins); 0 (Gelsolin); 0 (Pyrenes); 2ZD004190S (Threonine); 452VLY9402 (Serine); 9E0T7WFW93 (pyrene); EC 2.7.1.- (YopO protein, Yersinia enterocolitica); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170311
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.757971


  8 / 1547 MEDLINE  
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[PMID]:28213129
[Au] Autor:Wang CL; Wang H; Xiao F; Wang CD; Hu GL; Zhu JF; Shen C; Zuo B; Cui YM; Li; Yuan-Gao; Zhang XL; Chen XD
[Ad] Endereço:Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM), China.
[Ti] Título:Cyclic compressive stress-induced scinderin regulates progress of developmental dysplasia of the hip.
[So] Source:Biochem Biophys Res Commun;485(2):400-408, 2017 Apr 01.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Developmental dysplasia of the hip (DDH) is a common musculoskeletal disorder characterized by a mismatch between acetabulum and femoral head. Mechanical force plays an important role during the occurrence and development of abnormities in acetabulum and femoral head. In this study, we established a mechanical force model named cyclic compressive stress (Ccs). To analyze the effect of Ccs on DDH, we detected special genes in chondrocytes and osteoblasts. Results showed that Ccs downregulated chondrogenesis of ADTC5 in a concentration-dependent manner. Moreover, the mRNA level of Scinderin (Scin) considerably increased. We established lentivirus-SCIN(GV144-SCIN) to transfect hBMSCs, which were treated with different Ccs levels (0.25 Hz*5 cm, 0.5 Hz*5 cm, and 1 Hz*10 cm); the result showed that overexpression of Scin upregulated osteogenesis and osteoclastogenesis. By contrast, expression of chondrocyte-specific genes, including ACAN, COL-2A, and Sox9, decreased. Further molecular investigation demonstrated that Scin promoted osteogenesis and osteoclastogenesis through activation of the p-Smad1/5/8, NF-κB, and MAPK P38 signaling pathways, as well as stimulated the expression of key osteoclast transcriptional factors NFATc1 and c-Fos. Moreover, Scin-induced osteogenesis outweighed osteoclastogenesis in defective femur in vivo. The results of the analysis of Micro-CT confirmed these findings. Overall, Ccs influenced the development of DDH by promoting osteogenesis and cartilage degradation. In addition, Scin played a vital role in the development of DDH.
[Mh] Termos MeSH primário: Gelsolina/genética
Regulação da Expressão Gênica
Luxação Congênita de Quadril/genética
Estresse Mecânico
[Mh] Termos MeSH secundário: Animais
Western Blotting
Linhagem Celular Tumoral
Células Cultivadas
Condrócitos/metabolismo
Condrogênese/genética
Progressão da Doença
Gelsolina/metabolismo
Luxação Congênita de Quadril/metabolismo
Luxação Congênita de Quadril/patologia
Seres Humanos
Sistema de Sinalização das MAP Quinases
Transplante de Células-Tronco Mesenquimais
Células Mesenquimais Estromais/metabolismo
Camundongos Nus
NF-kappa B/metabolismo
Osteoblastos/metabolismo
Osteogênese/genética
Ratos
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Transplante Heterólogo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gelsolin); 0 (NF-kappa B); 0 (scinderin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170219
[St] Status:MEDLINE


  9 / 1547 MEDLINE  
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[PMID]:28208683
[Au] Autor:Zhang L; Han C; Ye F; He Y; Jin Y; Wang T; Wu Y; Jiang Y; Zhang F; Jin X
[Ad] Endereço:Department of Pathology, Harbin Medical University, Harbin 150081, China. Zhangleiyy12@126.com.
[Ti] Título:Plasma Gelsolin Induced Glomerular Fibrosis via the TGF-ß1/Smads Signal Transduction Pathway in IgA Nephropathy.
[So] Source:Int J Mol Sci;18(2), 2017 Feb 12.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Glomerular fibrosis has been shown to be closely related to the progression and prognosis of IgA nephropathy (IgAN). However, mechanism underlying IgAN glomerular fibrosis remains unclear. Recently, our study showed that plasma gelsolin (pGSN) was decreased in the serum of an IgAN mouse model and that pGSN deposition was found in the glomeruli. Another cytokine, TGF-ß1, which is closely related to glomerular fibrosis, was also found to be highly expressed in the glomeruli. In the present study, we report that pGSN induces glomerular fibrosis through the TGF-ß1/Smads signal transduction pathway. This is supported by the following findings: human mesangial cells (HMCs) show remarkable morphological changes and proliferation in response to co-stimulation with pGSN and polymeric IgA1 (pIgA1) from IgAN patients compared to other controls. Moreover, ELISA assays showed that more TGF-ß1 secretion was found in HMCs supernatants in the co-stimulation group. Further experiments showed increased TGF-ß1, Smad3, p-Smad2/3, Smad4, and collagen 1 and decreased Smad7 expression in the co-stimulation group. Our present study implied that the synergistic effect of pGSN and pIgA induced glomerular fibrosis via the TGF-ß1/Smads signal transduction pathway. This might be a potential mechanism for the glomerular fibrosis observed in IgAN patients.
[Mh] Termos MeSH primário: Gelsolina/sangue
Glomerulonefrite por IGA/metabolismo
Glomerulonefrite por IGA/patologia
Transdução de Sinais
Proteínas Smad/metabolismo
Fator de Crescimento Transformador beta1/metabolismo
[Mh] Termos MeSH secundário: Biomarcadores
Estudos de Casos e Controles
Proliferação Celular
Fibrose
Imunofluorescência
Glomerulonefrite por IGA/etiologia
Seres Humanos
Células Mesangiais/metabolismo
Células Mesangiais/patologia
Células Mesangiais/ultraestrutura
Fator de Crescimento Transformador beta1/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Gelsolin); 0 (Smad Proteins); 0 (Transforming Growth Factor beta1)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170420
[Lr] Data última revisão:
170420
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170218
[St] Status:MEDLINE


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[PMID]:28193690
[Au] Autor:Shao Z; Lee X; Huang G; Sheng G; Henderson CE; Louvard D; Sohn J; Pepinsky B; Mi S
[Ad] Endereço:Biogen, Inc., Cambridge, Massachusetts 02142.
[Ti] Título:LINGO-1 Regulates Oligodendrocyte Differentiation through the Cytoplasmic Gelsolin Signaling Pathway.
[So] Source:J Neurosci;37(12):3127-3137, 2017 Mar 22.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Differentiation and maturation of oligodendrocyte progenitor cells (OPCs) involve the assembly and disassembly of actin microfilaments. However, how actin dynamics are regulated during this process remains poorly understood. Leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1 (LINGO-1) is a negative regulator of OPC differentiation. We discovered that anti-LINGO-1 antibody-promoted OPC differentiation was accompanied by upregulation of cytoplasmic gelsolin (cGSN), an abundant actin-severing protein involved in the depolymerization of actin filaments. Treating rat OPCs with cGSN siRNA reduced OPC differentiation, whereas overexpression of cGSN promoted OPC differentiation and remyelination Furthermore, coexpression of cGSN and LINGO-1 blocked the inhibitory effect of LINGO-1. Our study demonstrates that cGSN works downstream of LINGO-1 signaling pathway, which enhances actin dynamics and is essential for OPC morphogenesis and differentiation. This finding may lead to novel therapeutic approaches for the treatment of demyelinating diseases such as multiple sclerosis (MS). Myelin loss and subsequent axon degeneration contributes to a variety of neurological diseases, such as multiple sclerosis (MS). Understanding the regulation of myelination by oligodendrocytes is therefore critical for developing therapies for the treatment of MS. We previously demonstrated that leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1 (LINGO-1) is a negative regulator of oligodendrocyte differentiation and that anti-LINGO-1 promotes remyelination in preclinical animal models for MS and in a phase II acute optic neuritis clinical trial (RENEW). The mechanism by which LINGO-1 regulates oligodendrocyte differentiation is unknown. Here, we demonstrate that LINGO-1 regulates oligodendrocyte differentiation and maturation through the cytoplasmic gelsolin signaling pathway, providing new drug targets for the treatment of demyelination diseases.
[Mh] Termos MeSH primário: Actinas/metabolismo
Diferenciação Celular/fisiologia
Gelsolina/metabolismo
Proteínas de Membrana/metabolismo
Proteínas do Tecido Nervoso/metabolismo
Oligodendroglia/citologia
Oligodendroglia/fisiologia
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Citoplasma/metabolismo
Feminino
Masculino
Camundongos
Ratos
Ratos Sprague-Dawley
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Gelsolin); 0 (LINGO1 protein, mouse); 0 (LINGO1 protein, rat); 0 (Membrane Proteins); 0 (Nerve Tissue Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170215
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.3722-16.2017



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