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1.
Proc Natl Acad Sci U S A ; 117(29): 17381-17388, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632018

RESUMO

Adiponectin (Acrp30) is an adipokine associated with protection from cardiovascular disease, insulin resistance, and inflammation. Although its effects are conventionally attributed to binding Adipor1/2 and T-cadherin, its abundance in circulation, role in ceramide metabolism, and homology to C1q suggest an overlooked role as a lipid-binding protein, possibly generalizable to other C1q/TNF-related proteins (CTRPs) and C1q family members. To investigate this, adiponectin, representative family members, and variants were expressed in Expi293 cells and tested for binding to lipids in liposomes using density centrifugation. Binding to physiological lipids were also analyzed using gradient ultracentrifugation, liquid chromatography-mass spectrometry, and shotgun lipidomics. Interestingly, adiponectin selectively bound several anionic phospholipids and sphingolipids, including phosphatidylserine, ceramide-1-phosphate, glucosylceramide, and sulfatide, via the C1q domain in an oligomerization-dependent fashion. Binding to lipids was observed in liposomes, low-density lipoproteins, cell membranes, and plasma. Other CTRPs and C1q family members (Cbln1, CTRP1, CTRP5, and CTRP13) also bound similar lipids. These findings suggest that adiponectin and CTRPs function not only as hormones, but also as lipid opsonins, as may other C1q family proteins.


Assuntos
Adiponectina/metabolismo , Complemento C1q/metabolismo , Fosfolipídeos/metabolismo , Esfingolipídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adipocinas/metabolismo , Adiponectina/genética , Animais , Ânions , Membrana Celular , LDL-Colesterol , Humanos , Metabolismo dos Lipídeos , Lipidômica , Lipoproteínas/metabolismo , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Opsonizantes/metabolismo , Plasma
4.
Expert Rev Cardiovasc Ther ; 18(6): 355-361, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32511037

RESUMO

INTRODUCTION: The prevalence of hypertriglyceridemia (HTG) is increasing. Elevated triglyceride (TG) levels are associated with an increased cardiovascular disease (CVD) risk. Moreover, severe HTG results in an elevated risk of pancreatitis, especially in severe HTG with an up to 350-fold increased risk. Both problems emphasize the clinical need for effective TG lowering. AREAS COVERED: The purpose of this review is to discuss the currently available therapies and to elaborate the most promising novel therapeutics for TG lowering. EXPERT OPINION: Conventional lipid lowering strategies do not efficiently lower plasma TG levels, leaving a residual CVD and pancreatitis risk. Both apolipoprotein C-III (apoC-III) and angiopoietin-like 3 (ANGPTL3) are important regulators in TG-rich lipoprotein (TRL) metabolism. Several novel agents targeting these linchpins have ended phase II/III trials. Volanesorsen targeting apoC-III has shown reductions in plasma TG levels up to 90%. Multiple ANGPLT3 inhibitors (evinacumab, IONIS-ANGPTL3-LRx, ARO-ANG3) effectuate TG reductions up to 70% with concomitant potent reduction in all other apoB containing lipoprotein fractions. We expect these therapeutics to become players in the treatment for (especially) severe HTG in the near future.


Assuntos
Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Apolipoproteína C-III/efeitos dos fármacos , Hipertrigliceridemia/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Ensaios Clínicos como Assunto , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/metabolismo , Lipoproteínas/metabolismo , Oligonucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , Pancreatite/etiologia , Pancreatite/prevenção & controle
5.
Int J Nanomedicine ; 15: 3433-3445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32523342

RESUMO

Background: Reconstituted lipoproteins (rLips) based on endogenous lipid nanostructures has been increasingly regarded as an excellent and promising antitumor drug delivery. However, some problems relating to the main component, apolipoprotein, for instance, rare source, unaffordable price, and low specificity of relevant receptor expression, become chief obstacles to its broad development and application. Purpose: The primary aim of this study is to develop biomimetic rLips by utilizing folic acid (FA)-modified bovine serum albumin (BSA) as a replacement for apolipoprotein and demonstrate its tumor targeting and antitumor efficacy. Methods: The amino groups of BSA were covalently conjugated with FA through the amide reaction. PTX-loaded nanostructured lipid carrier (termed as P-NLC) consisting of phospholipid, cholesteryl ester, triglyceride and cholesterol was prepared by the emulsification-evaporation method and utilized as the lipid core. FA-modified BSA (FA-BSA) was characterized for the protein substitute degree and attached with NLC by incubation-insert method to form the lipoprotein-mimic nanocomplex (termed as PFB-rLips). The morphology of nanoparticles was observed under transmission electron microscopy (TEM), and the particle size and zeta potential were determined using dynamic light scattering. In vitro release behavior of PTX from PFB-rLips was investigated with the dialysis method. Hemolysis tests were conducted to evaluate the biosecurity of PFB-rLips. Cell uptake and cytotoxicity assays were performed on human hepatocytes (LO2) and human hepatoma cells (HepG2). Tumor targeting was assessed using in vivo imaging system in H22 tumor-bearing mice model. Antitumor efficacy in vivo was investigated and compared between Taxol® (paclitaxel) formulation and PTX-incorporated nanoparticles in the same tumor model. Results: A fixed molar ratio 50:1 of FA to BSA was chosen as the optimal input ratio based on the balance between appropriate degree of protein substitution and amphiphilicity of FA-BSA. The morphology of FB-rLips exhibited as a homogeneous spherical structure featured by lipid cores surrounded with a cloudy protein shell observed under TEM. The particle size, zeta potential and encapsulation efficiency were 174.6±3.2 nm, -17.26±0.9 mV and 82.2±2.4%, respectively. In vitro release behavior of PTX from PFB-rLips was slow and sustained. The uptake of FB-rLips was much higher in HepG2 cells than in LO2 cells. Furthermore, the uptake of FB-rLips was significantly higher than that of rLips without FA involved (termed as B-rLips) and NLC in HepG2 cells. Hemolysis and cytotoxicity assays showed good biocompatibility of FB-rLips. The internalization mechanism of FB-rLips mainly depended on clathrin-mediated and caveolin-mediated endocytosis coupling with energy consumption, and FA receptors expressed on tumor cells played a critical role in cellular uptake process. CCK-8 studies demonstrated that PFB-rLips exhibited significantly better tumor killing ability than Taxol® (paclitaxel) formulation in vitro. Moreover, FB-rLips produced more excellent tumor-targeting properties than NLC through in vivo imaging assays. On the basis of this, PTX-loaded FB-rLips also performed more remarkable anticancer activity than other therapy groups in H22 tumor-bearing mice. Conclusion: FB-rLips would serve as a potential nanocarrier for improving tumor-targeting and therapeutic efficacy while reducing the side effects on normal tissues and organs.


Assuntos
Portadores de Fármacos/química , Ácido Fólico/uso terapêutico , Lipoproteínas/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Ácido Fólico/síntese química , Ácido Fólico/química , Hemólise/efeitos dos fármacos , Humanos , Camundongos , Nanopartículas/ultraestrutura , Neoplasias/patologia , Paclitaxel/química , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Tamanho da Partícula , Coelhos , Soroalbumina Bovina/química , Eletricidade Estática
6.
Sci Total Environ ; 739: 139982, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32544691

RESUMO

Fine particulate matter (PM2.5), which is known to impact public health, has received widespread attention recently. However, the long-term impact of maternal PM2.5 exposure remains unclear. To illuminate whether maternal PM2.5 exposure can affect serum lipoproteins and intestinal flora of offspring, mice received PM2.5 by intratracheal instillation during gestation and lactation. On postnatal day (PND) 35, serum lipoproteins of male and female pups were measured. Additionally, gut microbiota of offspring on PND 3, 10, 21 and 35 were measured by 16S rDNA sequencing of the colon contents. A higher serum triglyceride (TG) concentration in male offspring was observed in the exposed PM2.5 group (p < 0.05) compared with the control group, while there was no significant difference in lipoproteins for female offspring. On PND 35, Bacteroides, Desulfovibrio, and Anaerotruncus were enriched in the male offspring of the PM2.5-exposed group, and the control group had an increased abundance of Streptococcus. However, for female offspring on PND35, Clostridium XI was found to be enriched in the control group. A positive correlation between Bacteroides and serum TG concentration (r = 0.47, p = 0.02) was determined by Spearman's correlation analysis. These results suggest that serum TG and gut microbiota of offspring could be influenced by maternal PM2.5 exposure in a sex-specific manner. Abnormal lipid metabolism might be relevant to the changes of gut microbiota.


Assuntos
Microbioma Gastrointestinal , Efeitos Tardios da Exposição Pré-Natal , Animais , Bacteroides , Feminino , Humanos , Lipoproteínas , Masculino , Exposição Materna , Camundongos , Material Particulado
7.
PLoS Pathog ; 16(6): e1008597, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32511265

RESUMO

During infection of neurons by alphaherpesviruses including Pseudorabies virus (PRV) and Herpes simplex virus type 1 (HSV-1) viral nucleocapsids assemble in the cell nucleus, become enveloped in the cell body then traffic into and down axons to nerve termini for spread to adjacent epithelia. The viral membrane protein US9p and the membrane glycoprotein heterodimer gE/gI play critical roles in anterograde spread of both HSV-1 and PRV, and several models exist to explain their function. Biochemical studies suggest that PRV US9p associates with the kinesin-3 motor KIF1A in a gE/gI-stimulated manner, and the gE/gI-US9p complex has been proposed to recruit KIF1A to PRV for microtubule-mediated anterograde trafficking into or along the axon. However, as loss of gE/gI-US9p essentially abolishes delivery of alphaherpesviruses to the axon it is difficult to determine the microtubule-dependent trafficking properties and motor-composition of Δ(gE/gI-US9p) particles. Alternatively, studies in HSV-1 have suggested that gE/gI and US9p are required for the appearance of virions in the axon because they act upstream, to help assemble enveloped virions in the cell body. We prepared Δ(gE/gI-US9p) mutant, and control parental PRV particles from differentiated cultured neuronal or porcine kidney epithelial cells and quantitated the efficiency of virion assembly, the properties of microtubule-dependent transport and the ability of viral particles to recruit kinesin motors. We find that loss of gE/gI-US9p has no significant effect upon PRV particle assembly but leads to greatly diminished plus end-directed traffic, and enhanced minus end-directed and bidirectional movement along microtubules. PRV particles prepared from infected differentiated mouse CAD neurons were found to be associated with either kinesin KIF1A or kinesin KIF5C, but not both. Loss of gE/gI-US9p resulted in failure to recruit KIF1A and KF5C, but did not affect dynein binding. Unexpectedly, while KIF5C was expressed in undifferentiated and differentiated CAD neurons it was only found associated with PRV particles prepared from differentiated cells.


Assuntos
Herpesvirus Suídeo 1 , Peptídeos e Proteínas de Sinalização Intracelular , Cinesina/metabolismo , Lipoproteínas , Microtúbulos/metabolismo , Pseudorraiva , Proteínas do Envelope Viral , Proteínas Virais , Liberação de Vírus , Animais , Transporte Biológico Ativo , Linhagem Celular , Deleção de Genes , Herpesvirus Suídeo 1/genética , Herpesvirus Suídeo 1/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cinesina/genética , Lipoproteínas/genética , Lipoproteínas/metabolismo , Microtúbulos/genética , Microtúbulos/virologia , Pseudorraiva/genética , Pseudorraiva/metabolismo , Pseudorraiva/patologia , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo
8.
Medicine (Baltimore) ; 99(20): e20178, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443336

RESUMO

BACKGROUND: The objective of this study is to examine the association between serum lipoprotein levels (SLL) and cognitive impairment (CI) in patients with acute cerebral infarction (ACI). METHODS: All published studies will be searched from the following electronic databases: PubMed, EMBASE, Cochrane Library, PsycINFO, Web of Science, WANGFANG, and China National Knowledge Infrastructure from inauguration of each electronic database up to March 1, 2020. In addition, we will also search other sources, such as dissertations, Google scholar, conference proceedings, and reference lists of relevant reviews. We will not apply any language restrictions to the electronic databases. Two researchers will independently carry out literature selection, data collection, and methodological quality. A third researcher will help to solve any divergences by discussion. The RevMan 5.3 software will be employed to pool the collected data and to analyze the outcome data. RESULTS: This study will scrutinize the association between SLL and CI in patients with ACI. CONCLUSIONS: The results of this study will present helpful evidence of the association between SLL and CI in patients with ACI.Registration number: INPLASY202040018.


Assuntos
Isquemia Encefálica/patologia , Infarto Cerebral/complicações , Disfunção Cognitiva/etiologia , Lipoproteínas/sangue , Doença Aguda , Infarto Cerebral/epidemiologia , China/epidemiologia , Disfunção Cognitiva/sangue , Feminino , Humanos , Masculino , Sensibilidade e Especificidade
9.
Gene ; 749: 144720, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32360840

RESUMO

AIMS: The purpose of present study was to examine the correlations of LDL (LDLR) and HDL (SR-B1) receptors with lipoproteins, miR-199a-5p, miR-199b-5p, miR-455-5p in the malignant and benign breast tumors. METHODS: Total cholesterol-rich-lipoproteins and the receptors were determined using enzymatic-homogeneous and ELISA methods. The expression levels of miRNAs were detected by qRT-PCR. RESULTS: Receptor expressions and lipoproteins concentration were significantly higher in the malignant tumors (p < 0.05). Positive correlation was found for LDLR with Ki67% and Her2+. HDL-C content of TNBC tumors was higher than those of Non-TNBC (p < 0.05). The expression level of miR-199a-5p was found to be downregulated significantly in the malignant tumors of <2 cm, TNBC, HER2- or stage3. The expression of miR-199b-5p was downregulated in the malignant tumors and was negatively associated with TNBC, stage and Her2+. The expression of miR-455-5p was significantly correlated with Her2- (p < 0.05). A positive correlation was observed for SR-B1 or LDLR with HDL-C or LDL-C and also for SR-B1 with LDLR, although a reverse association was detected for the expression of miR-199b-5p with LDLR in the malignant tumors (p < 0.05). No significant correlations were found for miR-199a-5p or miR-455-5p with LDLR or SR-B1 expressions and also for LDL-C and SR-B1 with clinicopathological features (p ≥ 0.05). CONCLUSIONS: Mechanisms potentially involved in the present findings may be due to the lipid internalization and lipoprotein consumption through LDLR and SR-B1 over expression. It is noteworthy that the expression of miR-199b-5p is negatively correlated with LDLR which may suggest it as a suppressor for LDLR expression in the breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , MicroRNAs/metabolismo , Receptores de LDL/metabolismo , Receptores Depuradores Classe B/metabolismo , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Colesterol/metabolismo , Feminino , Humanos , Lipoproteínas/metabolismo , Pessoa de Meia-Idade
10.
Medicine (Baltimore) ; 99(20): e20258, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443365

RESUMO

BACKGROUND: The target of this study is to summarize the association between the serum lipoprotein levels and neurological function in patients with acute ischemic stroke. METHODS: A comprehensive search of Cochrane Library, PUBMED, EMBASE, Web of Science, and Chinese Biomedical Literature Database, China National Knowledge Infrastructure from inception to the February 29, 2020 without language and publication date restrictions. All searched studies will be selected by 2 authors independently against the eligibility criteria. Included studies will be critically appraised, and essential data will be extracted by 2 independent authors. If necessary, meta-analysis will be utilized to synthesize the outcome data from included articles. If it is not possible, a narrative synthesis will be undertaken. RESULTS: This study will summarize the up-to-date evidence to investigate the association between serum lipoprotein levels and neurological function in patients with acute ischemic stroke. CONCLUSION: Its results may present beneficial evidence and guidance for the clinical practice and further studies. STUDY REGISTRATION NUMBER: INPLASY202040043.


Assuntos
Isquemia Encefálica/complicações , Lipoproteínas/sangue , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/etiologia , Acidente Vascular Cerebral/complicações , Estudos de Casos e Controles , Humanos , Projetos de Pesquisa
11.
Proc Natl Acad Sci U S A ; 117(23): 13094-13104, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32434914

RESUMO

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. While the histopathology of the different disease stages is well characterized, the cause underlying the progression, from the early drusen stage to the advanced macular degeneration stage that leads to blindness, remains unknown. Here, we show that photoreceptors (PRs) of diseased individuals display increased expression of two key glycolytic genes, suggestive of a glucose shortage during disease. Mimicking aspects of this metabolic profile in PRs of wild-type mice by activation of the mammalian target of rapamycin complex 1 (mTORC1) caused early drusen-like pathologies, as well as advanced AMD-like pathologies. Mice with activated mTORC1 in PRs also displayed other early disease features, such as a delay in photoreceptor outer segment (POS) clearance and accumulation of lipofuscin in the retinal-pigmented epithelium (RPE) and of lipoproteins at the Bruch's membrane (BrM), as well as changes in complement accumulation. Interestingly, formation of drusen-like deposits was dependent on activation of mTORC1 in cones. Both major types of advanced AMD pathologies, including geographic atrophy (GA) and neovascular pathologies, were also seen. Finally, activated mTORC1 in PRs resulted in a threefold reduction in di-docosahexaenoic acid (DHA)-containing phospholipid species. Feeding mice a DHA-enriched diet alleviated most pathologies. The data recapitulate many aspects of the human disease, suggesting that metabolic adaptations in photoreceptors could contribute to disease progression in AMD. Identifying the changes downstream of mTORC1 that lead to advanced pathologies in mouse might present new opportunities to study the role of PRs in AMD pathogenesis.


Assuntos
Envelhecimento/patologia , Macula Lutea/patologia , Degeneração Macular/patologia , Células Fotorreceptoras Retinianas Cones/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Lâmina Basilar da Corioide/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Lipofuscina/metabolismo , Lipoproteínas/metabolismo , Macula Lutea/citologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Células Fotorreceptoras Retinianas Cones/metabolismo , Epitélio Pigmentado da Retina/metabolismo
13.
Gene ; 753: 144805, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32445923

RESUMO

Genomic variants in both ADTRP and TFPI genes are associated with risk of coronary artery disease (CAD). ADTRP regulates TFPI expression and endothelial cell functions involved in the initiation of atherosclerotic CAD. ADTRP also specifies primitive myelopoiesis and definitive hematopoiesis by upregulating TFPI expression. However, the underlying molecular mechanism is unknown. Here we show that transcription factor POU1F1 is the key by which ADTRP regulates TFPI expression. Luciferase reporter assays, chromatin-immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) in combination with analysis of large and small deletions of the TFPI promoter/regulatory region were used to identify the molecular mechanism by which ADTRP regulates TFPI expression. Genetic association was assessed using case-control association analysis and phenome-wide association analysis (PhenGWA). ADTRP regulates TFPI expression at the transcription level in a dose-dependent manner. The ADTRP-response element was localized to a 50 bp region between -806 bp and -756 bp upstream of TFPI transcription start site, which contains a binding site for POU1F1. Deletion of POU1F1-binding site or knockdown of POU1F1 expression abolished ADTRP-mediated transcription of TFPI. ChIP and EMSA demonstrated that POU1F1 binds to the ADTRP response element. Genetic analysis identified significant association between POU1F1 variants and risk of CAD. PhenGWA identified other phenotypic traits associated with the ADTRP-POU1F1-TFPI axis such as lymphocyte count (ADTRP), waist circumference (TFPI), and standing height (POU1F1). These data identify POU1F1 as a transcription factor that regulates TFPI transcription in response to ADTRP, and link POU1F1 variants to risk of CAD for the first time.


Assuntos
Doença da Artéria Coronariana/metabolismo , Lipoproteínas/biossíntese , Proteínas de Membrana/metabolismo , Fator de Transcrição Pit-1/metabolismo , Aterosclerose/genética , Estudos de Casos e Controles , Linhagem Celular , Imunoprecipitação da Cromatina/métodos , Doença da Artéria Coronariana/genética , Bases de Dados Genéticas , Células Endoteliais/metabolismo , Genes Homeobox , Células HeLa , Humanos , Lipoproteínas/genética , Lipoproteínas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Regiões Promotoras Genéticas , Elementos de Resposta , Sítio de Iniciação de Transcrição , Transcrição Genética
14.
Zhonghua Yi Xue Za Zhi ; 100(15): 1130-1135, 2020 Apr 21.
Artigo em Chinês | MEDLINE | ID: mdl-32311875

RESUMO

Objective: To explore the relationships between serum lipoprotein-associated phospholipase A2 (Lp-PLA2) and KIM-based white matter lesion (WML) and carotid atherosclerotic plaque. Methods: From November 2018 to July 2019, 155 patients admitted to the Department of Neurology of the First Affiliated Hospital of Anhui Medical University were enrolled, with 125 cases of brain MRI manifestations of white matter lesions allocated to WML group and 30 cases of normal MRI in control group (NC group). According to KIM classification, WML patients were further divided into juxtaventricular white matter lesion (JVWML) group (n=30), periventricular white matter lesion (PVWML) group (n=33), juxtacortical white matter lesion (JCWML) group (n=30) and deep white matter lesion (DWML) group (n=32). Clinical Data of vascular risk factors in all subjects was collected and reviewed. Serum Lp-PLA2 content was determined by double-antibody sandwich enzyme-linked immunosorbent assay (ELISA). Carotid atherosclerosis plaques were detected by carotid artery ultrasonography and divided into stable and vulnerable plaques, and thus total score of each plaque was subsequently calculated according to the Crouse method. Results: The Lp-PLA2 ((117±37) ng/ml vs (95±30) ng/ml), stable Crouse plaque integral (CPI) (0 (0,2.5) vs 0) and unstable CPI (0 (0,3.4) vs 0) in the WML group were significantly higher than those in the NC group (all P<0.05). Lp-PLA2 ((138±41) ng/ml) and unstable CPI (1.5(0,3.8)) in the PVWML group were significantly higher than those in the NC group (all P<0.05). Lp-PLA2 levels in the PVWML group were significantly higher than those in the JVWML group ((100±28) ng/ml) and JCWML group ((101±27) ng/ml) (all P<0.05). Correlation analysis revealed that blood glucose (r=0.600, P=0.000), triglyceride (TG) (r=0.371, P=0.034), low-density lipoprotein cholesterol (LDL-C) (r=0.367, P=0.036) and Lp-PLA2 (r=0.567, P=0.001) were positively correlated with unstable CPI in PVWML group, while it is negatively correlated with HDL-C (r=-0.368, P=0.035). Multivariate linear regression of all relevant factors and unstable CPI in the PVWML group showed that blood glucose (b=0.463, P<0.01) and Lp-PLA2 (b=0.347, P<0.05) were still positively correlated with unstable CPI. Conclusions: Serum Lp-PLA2 is an indicator of atherosclerosis, which is associated with carotid instability plaques in periventricular WML, suggesting that inflammatory mechanism plays an important role in the development of ischemic white matter lesions.


Assuntos
Placa Aterosclerótica , Substância Branca , 1-Alquil-2-acetilglicerofosfocolina Esterase , Aterosclerose , Biomarcadores , Humanos , Lipoproteínas , Fosfolipases A2
16.
Nat Commun ; 11(1): 1789, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286264

RESUMO

The mechanical properties of the cell envelope in Gram-negative bacteria are controlled by the peptidoglycan, the outer membrane, and the proteins interacting with both layers. In Escherichia coli, the lipoprotein Lpp provides the only covalent crosslink between the outer membrane and the peptidoglycan. Here, we use single-cell atomic force microscopy and genetically engineered strains to study the contribution of Lpp to cell envelope mechanics. We show that Lpp contributes to cell envelope stiffness in two ways: by covalently connecting the outer membrane to the peptidoglycan, and by controlling the width of the periplasmic space. Furthermore, mutations affecting Lpp function substantially increase bacterial susceptibility to the antibiotic vancomycin, indicating that Lpp-dependent effects can affect antibacterial drug efficacy.


Assuntos
Proteínas da Membrana Bacteriana Externa/metabolismo , Membrana Celular/metabolismo , Proteínas de Escherichia coli/metabolismo , Lipoproteínas/metabolismo , Antibacterianos/farmacologia , Bacteriologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Microscopia de Força Atômica , Peptidoglicano/metabolismo , Vancomicina/farmacologia
17.
Acta Crystallogr D Struct Biol ; 76(Pt 3): 221-237, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32133987

RESUMO

Fragment-based molecular-replacement methods can solve a macromolecular structure quasi-ab initio. ARCIMBOLDO, using a common secondary-structure or tertiary-structure template or a library of folds, locates these with Phaser and reveals the rest of the structure by density modification and autotracing in SHELXE. The latter stage is challenging when dealing with diffraction data at lower resolution, low solvent content, high ß-sheet composition or situations in which the initial fragments represent a low fraction of the total scattering or where their accuracy is low. SEQUENCE SLIDER aims to overcome these complications by extending the initial polyalanine fragment with side chains in a multisolution framework. Its use is illustrated on test cases and previously unknown structures. The selection and order of fragments to be extended follows the decrease in log-likelihood gain (LLG) calculated with Phaser upon the omission of each single fragment. When the starting substructure is derived from a remote homolog, sequence assignment to fragments is restricted by the original alignment. Otherwise, the secondary-structure prediction is matched to that found in fragments and traces. Sequence hypotheses are trialled in a brute-force approach through side-chain building and refinement. Scoring the refined models through their LLG in Phaser may allow discrimination of the correct sequence or filter the best partial structures for further density modification and autotracing. The default limits for the number of models to pursue are hardware dependent. In its most economic implementation, suitable for a single laptop, the main-chain trace is extended as polyserine rather than trialling models with different sequence assignments, which requires a grid or multicore machine. SEQUENCE SLIDER has been instrumental in solving two novel structures: that of MltC from 2.7 Šresolution data and that of a pneumococcal lipoprotein with 638 residues and 35% solvent content.


Assuntos
Cristalografia por Raios X/métodos , Fragmentos de Peptídeos/química , Peptídeos/química , Software , Algoritmos , Glicosiltransferases/química , Lipoproteínas/química , Dobramento de Proteína , Estrutura Secundária de Proteína
18.
Proc Natl Acad Sci U S A ; 117(12): 6777-6783, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32152098

RESUMO

Tol-Pal is a multiprotein system present in the envelope of Gram-negative bacteria. Inactivation of this widely conserved machinery compromises the outer membrane (OM) layer of these organisms, resulting in hypersensitivity to many antibiotics. Mutants in the tol-pal locus fail to complete division and form cell chains. This phenotype along with the localization of Tol-Pal components to the cytokinetic ring in Escherichia coli has led to the proposal that the primary function of the system is to promote OM constriction during division. Accordingly, a poorly constricted OM is believed to link the cell chains formed upon Tol-Pal inactivation. However, we show here that cell chains of E. coli tol-pal mutants are connected by an incompletely processed peptidoglycan (PG) layer. Genetic suppressors of this defect were isolated and found to overproduce OM lipoproteins capable of cleaving the glycan strands of PG. Among the factors promoting cell separation in mutant cells was a protein of previously unknown function (YddW), which we have identified as a divisome-localized glycosyl hydrolase that cleaves peptide-free PG glycans. Overall, our results indicate that the cell chaining defect of Tol-Pal mutants cannot simply be interpreted as a defect in OM constriction. Rather, the complex also appears to be required for the activity of several OM-localized enzymes with cell wall remodeling activity. Thus, the Tol-Pal system may play a more general role in coordinating OM invagination with PG remodeling at the division site than previously appreciated.


Assuntos
Proteínas da Membrana Bacteriana Externa/metabolismo , Divisão Celular , Parede Celular/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Lipoproteínas/metabolismo , Peptidoglicano/metabolismo , Proteínas da Membrana Bacteriana Externa/genética , Membrana Celular/metabolismo , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Proteínas de Escherichia coli/genética , Lipoproteínas/genética , Ligação Proteica
19.
Subcell Biochem ; 94: 35-62, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189295

RESUMO

Lipoproteins mediate the transport of apolar lipids in the hydrophilic environment of physiological fluids such as the vertebrate blood and the arthropod hemolymph. In this overview, we will focus on the hemolymph lipoproteins in Crustacea that have received most attention during the last years: the high density lipoprotein/ß-glucan binding proteins (HDL-BGBPs), the vitellogenins (VGs), the clotting proteins (CPs) and the more recently discovered large discoidal lipoproteins (dLPs). VGs are female specific lipoproteins which supply both proteins and lipids as storage material for the oocyte for later use by the developing embryo. Unusual within the invertebrates, the crustacean yolk proteins-formerly designated VGs-are more related to the ApoB type lipoproteins of vertebrates and are now termed apolipocrustaceins. The CPs on the other hand, which are present in both sexes, are related to the (sex specific) VGs of insects and vertebrates. CPs serve in hemostasis and wound closure but also as storage proteins in the oocyte. The HDL-BGBPs are the main lipid transporters, but are also involved in immune defense. Most crustacean lipoproteins belong to the family of the large lipid transfer proteins (LLTPs) such as the intracellular microsomal triglyceride transfer protein, the VGs, CPs and the dLPs. In contrast, the HDL-BGBPs do not belong to the LLTPs and their relationship with other lipoproteins is unknown. However, they originate from a common precursor with the dLPs, whose functions are as yet unknown. The majority of lipoprotein studies have focused on decapod crustaceans, especially shrimps, due to their economic importance. However, we will present evidence that the HDL-BGBPs are restricted to the decapod crustaceans which raises the question as to the main lipid transporting proteins of the other crustacean groups. The diversity of crustaceans lipoproteins thus appears to be more complex than reflected by the present state of knowledge.


Assuntos
Crustáceos , Hemolinfa , Lipoproteínas , Animais , Crustáceos/química , Crustáceos/imunologia , Crustáceos/metabolismo , Hemolinfa/química , Hemolinfa/imunologia , Hemolinfa/metabolismo , Lipoproteínas/biossíntese , Lipoproteínas/química , Lipoproteínas/imunologia , Lipoproteínas/metabolismo
20.
PLoS Genet ; 16(3): e1008605, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32150548

RESUMO

Circulating metabolite levels are biomarkers for cardiovascular disease (CVD). Here we studied, association of rare variants and 226 serum lipoproteins, lipids and amino acids in 7,142 (discovery plus follow-up) healthy participants. We leveraged the information from multiple metabolite measurements on the same participants to improve discovery in rare variant association analyses for gene-based and gene-set tests by incorporating correlated metabolites as covariates in the validation stage. Gene-based analysis corrected for the effective number of tests performed, confirmed established associations at APOB, APOC3, PAH, HAL and PCSK (p<1.32x10-7) and identified novel gene-trait associations at a lower stringency threshold with ACSL1, MYCN, FBXO36 and B4GALNT3 (p<2.5x10-6). Regulation of the pyruvate dehydrogenase (PDH) complex was associated for the first time, in gene-set analyses also corrected for effective number of tests, with IDL and LDL parameters, as well as circulating cholesterol (pMETASKAT<2.41x10-6). In conclusion, using an approach that leverages metabolite measurements obtained in the same participants, we identified novel loci and pathways involved in the regulation of these important metabolic biomarkers. As large-scale biobanks continue to amass sequencing and phenotypic information, analytical approaches such as ours will be useful to fully exploit the copious amounts of biological data generated in these efforts.


Assuntos
Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Variação Genética/genética , Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Lipoproteínas/sangue , Masculino , Fenótipo , Triglicerídeos/sangue
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