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1.
Acta Pharmacol Sin ; 2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32457417

RESUMO

Programmed cell death (PCD), including apoptosis, apoptotic necrosis, and pyroptosis, is involved in various organ dysfunction syndromes. Recent studies have revealed that a substrate of caspase-3, gasdermin E (GSDME), functions as an effector for pyroptosis; however, few inhibitors have been reported to prevent pyroptosis mediated by GSDME. Here, we developed a class of GSDME-derived inhibitors containing the core structure of DMPD or DMLD. Ac-DMPD-CMK and Ac-DMLD-CMK could directly bind to the catalytic domains of caspase-3 and specifically inhibit caspase-3 activity, exhibiting a lower IC50 than that of Z-DEVD-FMK. Functionally, Ac-DMPD/DMLD-CMK substantially inhibited both GSDME and PARP cleavage by caspase-3, preventing apoptotic and pyroptotic events in hepatocytes and macrophages. Furthermore, in a mouse model of bile duct ligation that mimics intrahepatic cholestasis-related acute hepatic failure, Ac-DMPD/DMLD-CMK significantly alleviated liver injury. Together, this study not only identified two specific inhibitors of caspase-3 for investigating PCD but also, more importantly, shed light on novel lead compounds for treating liver failure and organ dysfunctions caused by PCD.

2.
J Cell Biol ; 219(1)2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31653673

RESUMO

Lipid droplets (LDs) are evolutionarily conserved organelles that play important roles in cellular metabolism. Each LD is enclosed by a monolayer of phospholipids, distinct from bilayer membranes. During LD biogenesis and growth, this monolayer of lipids expands by acquiring phospholipids from the endoplasmic reticulum (ER) through nonvesicular mechanisms. Here, in a mini-screen, we find that ORP5, an integral membrane protein of the ER, can localize to ER-LD contact sites upon oleate loading. ORP5 interacts with LDs through its ligand-binding domain, and ORP5 deficiency enhances neutral lipid synthesis and increases the size of LDs. Importantly, there is significantly more phosphatidylinositol-4-phosphate (PI(4)P) and less phosphatidylserine (PS) on LDs in ORP5-deficient cells than in normal cells. The increased presence of PI(4)P on LDs in ORP5-deficient cells requires phosphatidylinositol 4-kinase 2-α. Our results thus demonstrate the existence of PI(4)P on LDs and suggest that LD-associated PI(4)P may be primarily used by ORP5 to deliver PS to LDs.

3.
Cardiovasc Diagn Ther ; 9(5): 462-471, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31737517

RESUMO

Background: For hemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI) who missed the reperfusion window, optimal timing for delayed revascularization remains controversial. Methods: We investigated 7,698 consecutive patients without cardiogenic shock, serious heart failure, or thrombolysis who underwent delayed stenting (12 hours to 28 days after STEMI) at multiple centers in China. The patients were divided according to delayed PCI timing into very early (12-72 hours), early (3-7 days), intermediate (7-14 days) and late (14-28 days) groups. The primary outcome was in-hospital rate of major adverse cardiovascular events (MACE); secondary outcomes were in-hospital rates of all bleeding events, heart failure and sudden cardiac arrest (SCA). All endpoint events were a composite of the primary and secondary endpoints. Results: In-hospital MACE rate was similar among groups (P=0.588). Patients who underwent late vs. very early, early and intermediate delayed PCI had higher in-hospital rates of secondary events (13% vs. 8.0%, 8.1% and 0.3%, P<0.001) and heart failure (11.8% vs. 6.2%, 6.3% and 7.6%, P<0.001, respectively). For all in-hospital events, the late vs. intermediate group was at higher risk (OR =1.26, 95% CI: 1.02 to 1.56, P=0.029); and in subgroup analysis, patients with Killip class II or III heart failure had similar rates (OR =1.02, 95% CI: 0.74 to 1.40, P=0.908); while women (OR =1.67, 95% CI: 1.07 to 2.62, P=0.024), and smokers (OR =1.46, 95% CI: 1.05 to 2.02, P=0.023) had higher rates. Conclusions: Late delayed PCI (14-28 days) after STEMI was associated with a higher incidence of in-hospital adverse events particularly in women and smokers but not with Killip class II-III heart failure, which might allow medical treatment to improve function.

4.
Research (Wash D C) ; 2019: 2602414, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31549053

RESUMO

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a promising target for drug and pesticide discovery. The unknown binding mode of substrate is still a big challenge for the understanding of enzymatic reaction mechanism and novel HPPD inhibitor design. Herein, we determined the first crystal structure of Arabidopsis thaliana HPPD (AtHPPD) in complex with its natural substrate (HPPA) at a resolution of 2.80 Å. Then, combination of hybrid quantum mechanics/molecular mechanics (QM/MM) calculations confirmed that HPPA takes keto rather than enol form inside the HPPD active pocket. Subsequent site-directed mutagenesis and kinetic analysis further showed that residues (Phe424, Asn423, Glu394, Gln307, Asn282, and Ser267) played important roles in substrate binding and catalytic cycle. Structural comparison between HPPA-AtHPPD and holo-AtHPPD revealed that Gln293 underwent a remarkable rotation upon the HPPA binding and formed H-bond network of Ser267-Asn282-Gln307-Gln293, resulting in the transformation of HPPD from an inactive state to active state. Finally, taking the conformation change of Gln293 as a target, we proposed a new strategy of blocking the transformation of HPPD from inactive state to active state to design a novel inhibitor with K i value of 24.10 nM towards AtHPPD. The inhibitor has entered into industry development as the first selective herbicide used for the weed control in sorghum field. The crystal structure of AtHPPD in complex with the inhibitor (2.40 Å) confirmed the rationality of the design strategy. We believe that the present work provides a new starting point for the understanding of enzymatic reaction mechanism and the design of next generation HPPD inhibitors.

5.
Zool Res ; 40(5): 456-465, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31502428

RESUMO

Mountain Dragons of the genus Diploderma Hallowell, 1861 were recently resurrected from the paraphyletic genus Japalura sensu lato (Wang et al., 2019a). Despite the recent split, Diploderma still represents one of the most diverse groups of agamid lizard from Asia, including 25 species recognized currently, with most species found in China ((Wang et al., 2019a, 2019b). Although increasing attention has been paid to cryptic diversity within the genus in Southwest China during the past decade, most studies have focused on a single species complex, D. flaviceps, only (Manthey et al., 2012; Wang et al., 2015, 2016, 2017, 2019a), with few studies on other congeners that also have widespread distributions. One such example is D. dymondi (Boulenger, 1906).


Assuntos
Distribuição Animal , Lagartos/classificação , Animais , China , DNA Mitocondrial/genética , Feminino , Lagartos/genética , Masculino , Filogenia , Especificidade da Espécie
6.
J Biomol Struct Dyn ; : 1-14, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31345118

RESUMO

In this study, we aimed to identify critical factors associated with superoxide dismutase 2 (SOD2) in human keratinocytes through gene and protein expression profiling approaches. After recombinant SOD2 was exogenously added to culture media, we conducted serial OMICS studies, which included RNA sequencing analysis, integrated antibody-chip arrays, and the implementation of bioinformatics algorithms, in order to reveal genes and proteins that are possibly associated with SOD2 in keratinocytes. These approaches identified several novel genes and proteins in keratinocytes that are associated with exogenous SOD2. These novel genes included DCT, which was up-regulated, and CD38, GPR151, HCK, KIT, and AFP, which were down-regulated. Among them, CD38 and KIT were also predicted as hub proteins in PPI mappings. By integrating the datasets obtained from these complementary high-throughput OMICS studies and utilizing the strengths of each method, we obtained new insights into the functional role of externally added SOD2 in skin cells and into several critical genes that are thought to play important roles in SOD2-associated skin function. The approach used here could help contribute to our clinical understanding of SOD2-associated applications and may be broadly applicable to a wider range of diseases. Abbreviations SOD2 superoxide dismutase 2 DAVID the database for annotation, visualization and integrated discovery KEGG Kyoto Encyclopedia of Genes and Genomes PPI protein-protein interactions HTS High-throughput screening Communicated by Ramaswamy H. Sarma.

7.
Nat Commun ; 10(1): 829, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30783101

RESUMO

Phosphatidylinositol phosphates (PIPs) and cholesterol are known to regulate the function of late endosomes and lysosomes (LELs), and ORP1L specifically localizes to LELs. Here, we show in vitro that ORP1 is a PI(4,5)P2- or PI(3,4)P2-dependent cholesterol transporter, but cannot transport any PIPs. In cells, both ORP1L and PI(3,4)P2 are required for the efficient removal of cholesterol from LELs. Structures of the lipid-binding domain of ORP1 (ORP1-ORD) in complex with cholesterol or PI(4,5)P2 display open conformations essential for ORP function. PI(4,5)P2/PI(3,4)P2 can facilitate ORP1-mediated cholesterol transport by promoting membrane targeting and cholesterol extraction. Thus, our work unveils a distinct mechanism by which PIPs may allosterically enhance OSBP/ORPs-mediated transport of major lipid species such as cholesterol.


Assuntos
Colesterol/metabolismo , Fosfatidilinositóis/metabolismo , Receptores de Esteroides/química , Receptores de Esteroides/metabolismo , Regulação Alostérica , Sítios de Ligação , Transporte Biológico , Membrana Celular/metabolismo , Cristalografia por Raios X , Endossomos/metabolismo , Células HEK293 , Humanos , Lisossomos/metabolismo , Mutação , Receptores de Esteroides/genética , Esteróis/metabolismo
8.
FEBS J ; 286(5): 975-990, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30632699

RESUMO

Slow-binding inhibitors with long residence time on the target often display superior efficacy in vivo. Rationally designing inhibitors with low off-target rates is restricted by a limited understanding of the structural basis of slow-binding inhibition kinetics in enzyme-drug interactions. 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for drug and herbicide development. Although the time-dependent behavior of HPPD inhibitors has been studied for decades, its structural basis and mechanism remain unclear. Herein, we report a detailed experimental and computational study that explores structures for illustrating the slow-binding inhibition kinetics of HPPD. We observed the conformational change of Phe428 at the C-terminal α-helix in the inhibitor-bound structures and further identified that the inhibition kinetics of drugs are related to steric hindrance of Phe428. These detailed structural and mechanistic insights illustrate that steric hindrance is highly associated with the time-dependent behavior of HPPD inhibitors. These findings may enable rational design of new potent HPPD-targeted drugs or herbicides with longer target residence time and improved properties. DATABASE: Structure data are available in the PDB under the accession numbers 5CTO (released), 5DHW (released), and 5YWG (released).


Assuntos
4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores , Simulação por Computador , 4-Hidroxifenilpiruvato Dioxigenase/química , Sequência de Aminoácidos , Cristalografia por Raios X , Cicloexanonas/química , Inibidores Enzimáticos/química , Herbicidas/química , Cinética , Mesilatos/química , Estrutura Molecular , Nitrobenzoatos/química , Homologia de Sequência de Aminoácidos
9.
FEBS J ; 286(5): 1030-1052, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30663248

RESUMO

Bistability (coexistence of two stable steady states in a dynamical system) is a key mechanism of cellular decision-making and has been observed in many biochemical reaction networks such as mitogen-activated protein kinase (MAPK) signaling pathways. Theoretical studies have shown that bistability can arise in a single two-site MAPK phosphorylation and dephosphorylation cycle. However, the bistable behavior mostly relies on the kinetic mechanisms and parameters of this two-site modification. In exploring the system-level properties of MAPK regulation, most models to date focus on two limiting reaction regimes, distributive and processive, and are characterized by high levels of parametric uncertainty. Here, we developed a combined kinetic method which applies a continuous spectrophotometric enzyme-coupled assay incorporated with the viscosity approach, to perform detailed kinetic analyses of p38α MAPK dual phosphorylation by MKK6. Almost all kinetic rate constants for the first and second phosphorylation steps in p38α activation have been quantitatively determined, supporting that the phosphorylation occurs randomly in the first step, albeit preferring the tyrosine residue. The release rates of monophosphorylated p38α from MKK6, either as the product in the first modification or as the substrate in the second step, were comparable to the respective adjacent phosphoryl transfer steps. These results indicated that dual phosphorylation of p38α by MKK6 involves a random, partially processive mechanism. Based on the experimentally determined models and parameters, dynamics of the p38α-MKK6-MKP5 system were explored, demonstrating for the first time that bistability can arise with this model at biologically feasible parameter values. ENZYMES: p38α (EC 2.7.11.24); MKK6 (EC 2.7.12.2).


Assuntos
MAP Quinase Quinase 6/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Humanos , Cinética , Fosforilação , Espectrofotometria/métodos , Especificidade por Substrato
11.
Mol Cell ; 73(3): 458-473.e7, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30581148

RESUMO

Cholesterol is highly enriched at the plasma membrane (PM), and lipid transfer proteins may deliver cholesterol to the PM in a nonvesicular manner. Here, through a mini-screen, we identified the oxysterol binding protein (OSBP)-related protein 2 (ORP2) as a novel mediator of selective cholesterol delivery to the PM. Interestingly, ORP2-mediated enrichment of PM cholesterol was coupled with the removal of phosphatidylinositol 4, 5-bisphosphate (PI(4,5)P2) from the PM. ORP2 overexpression or deficiency impacted the levels of PM cholesterol and PI(4,5)P2, and ORP2 efficiently transferred both cholesterol and PI(4,5)P2in vitro. We determined the structure of ORP2 in complex with PI(4,5)P2 at 2.7 Å resolution. ORP2 formed a stable tetramer in the presence of PI(4,5)P2, and tetramerization was required for ORP2 to transfer PI(4,5)P2. Our results identify a novel pathway for cholesterol delivery to the PM and establish ORP2 as a key regulator of both cholesterol and PI(4,5)P2 of the PM.


Assuntos
Membrana Celular/metabolismo , Colesterol/metabolismo , Hepatócitos/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Receptores de Esteroides/metabolismo , Transporte Biológico , Linhagem Celular Tumoral , Células HEK293 , Humanos , Modelos Moleculares , Multimerização Proteica , Estrutura Quaternária de Proteína , Receptores de Esteroides/química , Receptores de Esteroides/genética , Relação Estrutura-Atividade
12.
Nucleic Acids Res ; 46(9): 4771-4782, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29490074

RESUMO

Specific manipulation of RNA is necessary for the research in biotechnology and medicine. The RNA-binding domains of Pumilio/fem-3 mRNA binding factors (PUF domains) are programmable RNA binding scaffolds used to engineer artificial proteins that specifically modulate RNAs. However, the native PUF domains generally recognize 8-nt RNAs, limiting their applications. Here, we modify the PUF domain of human Pumilio1 to engineer PUFs that recognize RNA targets of different length. The engineered PUFs bind to their RNA targets specifically and PUFs with more repeats have higher binding affinity than the canonical eight-repeat domains; however, the binding affinity reaches the peak at those with 9 and 10 repeats. Structural analysis on PUF with nine repeats reveals a higher degree of curvature, and the RNA binding unexpectedly and dramatically opens the curved structure. Investigation of the residues positioned in between two RNA bases demonstrates that tyrosine and arginine have favored stacking interactions. Further tests on the availability of the engineered PUFs in vitro and in splicing function assays indicate that our engineered PUFs bind RNA targets with high affinity in a programmable way.


Assuntos
Domínios Proteicos , Engenharia de Proteínas , Proteínas de Ligação a RNA/química , RNA/química , Processamento Alternativo , Arginina/química , Sequência de Bases , Humanos , Modelos Moleculares , Ligação Proteica , RNA/metabolismo , Tirosina/química
13.
Dalton Trans ; 47(7): 2143-2147, 2018 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-29372734

RESUMO

A new 3D MOF [MnLi2(ip)2(H2O)2] (1) with a 1D heterometallic inorganic Mn(ii)-Li(i) chain is reported. With the assistance of diamagnetic {LiO4} connectors, which separate the paramagnetic Mn(ii) ions and act as magnetic spacers, very weak magnetic interactions were obtained. Remarkably, 1 showed a significant magnetocaloric effect (MCE) with a large entropy change value of 30.4 J kg-1 K-1 for ΔH = 8 T at 2 K.

14.
Biochem Biophys Res Commun ; 495(1): 1-6, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29061304

RESUMO

Sucrose non-fermenting (Snf1)-related kinase (SNRK) is a novel member of the AMP-activated protein kinase (AMPK) family and is involved in many metabolic processes. Here we report the crystal structure of an N-terminal SNRK fragment containing kinase and adjacent ubiquitin-associated (UBA) domains. This structure shows that the UBA domain binds between the N- and C-lobes of the kinase domain. The mode of UBA binding in SNRK largely resembles that in AMPK and brain specific kinase (BRSK), however, unique interactions play vital roles in stabilizing the KD-UBA interface of SNRK. We further propose a potential role of the UBA domain in the regulation of SNRK kinase activity. This study provides new insights into the structural diversities of the AMPK kinase family.


Assuntos
Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases Ativadas por AMP/química , Proteínas Quinases Ativadas por AMP/metabolismo , Sequência de Aminoácidos , Animais , Domínio Catalítico , Cristalografia por Raios X , Humanos , Modelos Moleculares , Domínios Proteicos , Proteínas Serina-Treonina Quinases/genética , Receptor EphA5/química , Receptor EphA5/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Ubiquitina/metabolismo
15.
Biochemistry ; 56(46): 6165-6175, 2017 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-29077400

RESUMO

The mitogen-activated protein kinases (MAPKs) are key components of cellular signal transduction pathways, which are down-regulated by the MAPK phosphatases (MKPs). Catalytic activity of the MKPs is controlled both by their ability to recognize selective MAPKs and by allosteric activation upon binding to MAPK substrates. Here, we use a combination of experimental and computational techniques to elucidate the molecular mechanism for the ERK2-induced MKP3 activation. Mutational and kinetic study shows that the 334FNFM337 motif in the MKP3 catalytic domain is essential for MKP3-mediated ERK2 inactivation and is responsible for ERK2-mediated MKP3 activation. The long-term molecular dynamics (MD) simulations further reveal a complete dynamic process in which the catalytic domain of MKP3 gradually changes to a conformation that resembles an active MKP catalytic domain over the time scale of the simulation, providing a direct time-dependent observation of allosteric signal transmission in ERK2-induced MKP3 activation.


Assuntos
Fosfatase 6 de Especificidade Dupla/metabolismo , Ativação Enzimática , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Transdução de Sinais , Regulação Alostérica , Animais , Domínio Catalítico , Fosfatase 6 de Especificidade Dupla/química , Humanos , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/química , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Ratos
16.
Nat Commun ; 8(1): 757, 2017 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-28970484

RESUMO

ORP5 and ORP8, members of the oxysterol-binding protein (OSBP)-related proteins (ORP) family, are endoplasmic reticulum membrane proteins implicated in lipid trafficking. ORP5 and ORP8 are reported to localize to endoplasmic reticulum-plasma membrane junctions via binding to phosphatidylinositol-4-phosphate (PtdIns(4)P), and act as a PtdIns(4)P/phosphatidylserine counter exchanger between the endoplasmic reticulum and plasma membrane. Here we provide evidence that the pleckstrin homology domain of ORP5/8 via PtdIns(4,5)P 2, and not PtdIns(4)P binding mediates the recruitment of ORP5/8 to endoplasmic reticulum-plasma membrane contact sites. The OSBP-related domain of ORP8 can extract and transport multiple phosphoinositides in vitro, and knocking down both ORP5 and ORP8 in cells increases the plasma membrane level of PtdIns(4,5)P 2 with little effect on PtdIns(4)P. Overall, our data show, for the first time, that phosphoinositides other than PtdIns(4)P can also serve as co-exchangers for the transport of cargo lipids by ORPs.ORP5/8 are endoplasmic reticulum (ER) membrane proteins implicated in lipid trafficking that localize to ER-plasma membrane (PM) contacts and maintain membrane homeostasis. Here the authors show that PtdIns(4,5)P 2 plays a critical role in the targeting and function of ORP5/8 at the PM.


Assuntos
Membrana Celular/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Receptores de Esteroides/metabolismo , Transporte Biológico , Retículo Endoplasmático/metabolismo , Células HeLa , Humanos , Metabolismo dos Lipídeos , Fosfatos de Fosfatidilinositol/metabolismo , Fosfatidilserinas/metabolismo
17.
Dev Cell ; 41(1): 107-120.e4, 2017 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-28399395

RESUMO

Cell-cell fusion generally requires cellular fusogenic proteins and actin-propelled membrane protrusions. However, the molecular connections between fusogens and the actin cytoskeleton remain unclear. Here, we show that the Caenorhabditis elegans fusogen EFF-1 and F-actin are enriched at the cortex of the post-embryonic fusing cells, and conditional mutations of WASP and Arp2/3 delay cell-cell fusion by impairing EFF-1 localization. Our affinity purification and mass spectrometry analyses determined that an actin-binding protein, spectraplakin/VAB-10A, binds to EFF-1. VAB-10A promotes cell-cell fusion by linking EFF-1 to the actin cytoskeleton. Conversely, EFF-1 enhanced the F-actin bundling activity of VAB-10A in vitro, and actin dynamics in the cortex were reduced in eff-1 or vab-10a mutants. Thus, cell-cell fusion is promoted by a positive feedback loop in which actin filaments that are crosslinked by spectraplakin to recruit fusogens to fusion sites are reinforced via fusogens, thereby increasing the probability of further fusogen accumulation to form fusion synapses.


Assuntos
Citoesqueleto de Actina/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/citologia , Caenorhabditis elegans/metabolismo , Retroalimentação Fisiológica , Glicoproteínas de Membrana/metabolismo , Complexo 2-3 de Proteínas Relacionadas à Actina , Actinas/metabolismo , Animais , Fusão Celular , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Larva/citologia , Larva/metabolismo , Ligação Proteica , Estabilidade Proteica , Transporte Proteico , Proteína da Síndrome de Wiskott-Aldrich
19.
J Huazhong Univ Sci Technolog Med Sci ; 36(6): 859-864, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27924511

RESUMO

Pleural effusion after hepatectomy is associated with significant morbidity and prolonged hospital stays. Several studies have addressed the risk factors for postoperative pleural effusion. However, there are no researches concerning the role of the initial 12-h operative fluid volume. The aim of this study was to evaluate whether the initial 12-h operative fluid volume during liver resection is an independent risk factor for pleural effusion after hepatectomy. In this study, we retrospectively analyzed clinical data of 470 patients consecutively undergoing elective hepatectomy between January 2011 and December 2012. We prospectively collected and retrospectively analyzed baseline and clinical data, including preoperative, intraoperative, and postoperative variables. Univariate and multivariate analyses were carried out to identify whether the initial 12-h operative fluid volume was an independent risk factor for pleural effusion after hepatectomy. The multivariate analysis identified 2 independent risk factors for pleural effusion: operative time [odds ratio (OR)=10.2] and initial 12-h operative fluid volume (OR=1.0003). Threshold effect analyses revealed that the initial 12 h operative fluid volume was positively correlated with the incidence of pleural effusion when the initial 12-h operative fluid volume exceeded 4636 mL. We conclude that the initial 12-h operative fluid volume during liver resection and operative time are independent risk factors for pleural effusion after hepatectomy. Perioperative intravenous fluids should be restricted properly.


Assuntos
Hidratação/efeitos adversos , Hepatectomia/efeitos adversos , Derrame Pleural/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Soluções para Reidratação/efeitos adversos , Adulto , Idoso , Feminino , Hepatectomia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Derrame Pleural/etiologia , Complicações Pós-Operatórias/etiologia , Soluções para Reidratação/administração & dosagem
20.
Dev Cell ; 39(2): 224-238, 2016 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-27780040

RESUMO

Directional cell migration is critical for metazoan development. We define two molecular pathways that activate the Arp2/3 complex during neuroblast migration in Caenorhabditis elegans. The transmembrane protein MIG-13/Lrp12 is linked to the Arp2/3 nucleation-promoting factors WAVE or WASP through direct interactions with ABL-1 or SEM-5/Grb2, respectively. WAVE mutations partially impaired F-actin organization and decelerated cell migration, and WASP mutations did not inhibit cell migration but enhanced migration defects in WAVE-deficient cells. Purified SEM-5 and MIG-2 synergistically stimulated the F-actin branching activity of WASP-Arp2/3 in vitro. In GFP knockin animals, WAVE and WASP were largely organized into separate clusters at the leading edge, and the amount of WASP was less than WAVE but could be elevated by WAVE mutations. Our results indicate that the MIG-13-WAVE pathway provides the major force for directional cell motility, whereas MIG-13-WASP partially compensates for its loss, underscoring their coordinated activities in facilitating robust cell migration.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/citologia , Caenorhabditis elegans/metabolismo , Movimento Celular , Neurônios/citologia , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Citoesqueleto de Actina/metabolismo , Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Animais , Proteínas de Membrana/metabolismo , Modelos Biológicos , Ligação Proteica , Pseudópodes/metabolismo
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