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1.
Artigo em Inglês | MEDLINE | ID: mdl-31800128

RESUMO

RATIONALE: With the recent introduction of the dynamically harmonized cell, the complexity of tuning has expanded drastically, and fine-tuning of the DC voltages is required to optimize the ion cloud movement. As this adjustment has typically to be performed manually, more reliable computational methods would be usefil. METHODS: Here, we propose a computational method based on a design of experiments (DoE) strategy to overcome the limits of classical manual tuning. This DoE strategy was exemplarily applied on a 12T FTICR equipped with a dynamically harmonized ICR cell. The chemometric approach, based on a composite central face design (CCF), was first applied on a reference material (sodium trifluoroacetate) allowing for the evaluation of the primary cell parameters. Eight factors were identified related to shimming and gating. The summed intensity of the signal corresponding to the even harmonics was defined as one quality criterion. RESULTS: The DoE response allowed for rapid and complete mapping of cell parameters resulting in an optimized parameter set. The new set of cell parameters was applied to the study of an ultra-complex sample: Tholins, an ultra-complex mixture that mimics the haze present on Titan, was chosen. We observed a substantial improvement in mass spectrometric performance. The sum of signals related to harmonics was decreased by a factor of three (from 4% for conventional tuning to 1.3%). Furthermore, the dynamic range was also increased and this led to an increase of attributed peaks by 13%. CONCLUSIONS: This computational procedure based on an experimental design can be applied for any other mass spectrometric parameter optimization problem. This strategy will lead more transparent and data-driven method development.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31783433

RESUMO

RATIONALE: Quadrupole mass spectrometers equipped with an Electron Ionization (EI) sources have been widely used in space exploration to investigate the composition of planetary surfaces and atmospheres. However, the complexity of the samples and the minimal calibration for the fragmentation of molecules in the ionization chambers have prevented the deconvolution of the majority of the mass spectra obtained at different targets, thus limiting determination of the exact composition of the samples analyzed. We propose a Monte-Carlo approach to solve this issue mathematically. METHODS: We have decomposed simulated mass spectra of mixtures acquired with unit resolving power mass spectrometers and EI sources into the sum of the single components fragmentation patterns weighted by their relative concentration using interior-point least-square fitting. To fit compounds with poorly known fragmentation patterns, we use a Monte-Carlo method to vary the intensity of individual fragment ions. We then decompose the spectrum thousands of times to obtain a statistical distribution. RESULTS: By performing the deconvolution on a mixture of seven different molecules with interfering fragmentation patterns (H2 O, O2 , CH4 , Ar, N2 , C2 H4 and C2 H6 ) we show that this approach retrieves the mixing ratio of the individual components more accurately than regular mass spectra decomposition methods that rely on fragmentation patterns from general databases. It also provides the probability density function for each species's mixing ratio. CONCLUSIONS: By removing the solution degeneracy in the decomposition of mass spectra, the method described herein could significantly increase the scientific retrieval from archived space flight mass spectrometry data, where calibration of the ionization source is no longer an option.

3.
Front Microbiol ; 10: 1774, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428071

RESUMO

Lipopolysaccharides (LPS) originate from the outer membrane of Gram-negative bacteria and trigger an inflammatory response via the innate immune system. LPS consist of a lipid A moiety directly responsible for the stimulation of the proinflammatory cascade and a polysaccharide chain of variable length. LPS form aggregates of variable size and structure in aqueous media, and the aggregation/disaggregation propensity of LPS is known as a key determinant of their biological activity. The aim of the present study was to determine to which extent the length of the polysaccharide chain can affect the nature of LPS structures, their pharmacokinetics, and eventually their proinflammatory properties in vivo. LPS variants of Salmonella Minnesota with identical lipid A but with different polysaccharide moieties were used. The physical properties of LPS aggregates were analyzed by zetametry, dynamic light scattering, and microscopy. The stability of LPS aggregates was tested in the presence of plasma, whole blood, and cultured cell lines. LPS pharmacokinetics was performed in wild-type mice. The accumulation in plasma of rough LPS (R-LPS) with a short polysaccharidic chain was lower, and its hepatic uptake was faster as compared to smooth LPS (S-LPS) with a long polysaccharidic chain. The inflammatory response was weaker with R-LPS than with S-LPS. As compared to S-LPS, R-LPS formed larger aggregates, with a higher hydrophobicity index, a more negative zeta potential, and a higher critical aggregation concentration. The lower stability of R-LPS aggregates could be illustrated in vitro by a higher extent of association of LPS to plasma lipoproteins, faster binding to blood cells, and increased uptake by macrophages and hepatocytes, compared to S-LPS. Our data indicate that a long polysaccharide chain is associated with the formation of more stable aggregates with extended residence time in plasma and higher inflammatory potential. These results show that polysaccharide chain length, and overall aggregability of LPS might be helpful to predict the proinflammatory effect that can be expected in experimental settings using LPS preparations. In addition, better knowledge and control of LPS aggregation and disaggregation might lead to new strategies to enhance LPS detoxification in septic patients.

4.
Obes Surg ; 29(9): 2843-2853, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31183785

RESUMO

BACKGROUND: The aim of this study was to investigate whether the implementation of enhanced recovery after surgery (ERAS) guidelines according to Thorell and co. in our tertiary referral bariatric center might improve post-operative outcomes. METHODS: ERAS program was introduced in our center since January 1, 2017. Retrospective review of a prospectively collected database identified patients who underwent laparoscopic primary and revisional bariatric surgeries from October 2005 to January 2018. Patients exposed to ERAS program ("ERAS group") were matched in a 1:1 ratio with patients exposed to conventional care (control group) using a propensity score based on age, gender, preoperative body mass index (BMI), diabetes mellitus, and the type of procedures. The primary outcome was total hospital length of stay (LOS) and the secondary outcomes included the post-operative complications and readmission rates. RESULTS: During the study period, 464 patients were included, 232 in each group. Implementation of the ERAS protocol was significantly associated with a reduction of LOS (2.47 ± 1.7 vs 5.39 ± 1.9 days, p < 0.00001). One-third of patients was discharged (77/232, 33%) on the first postoperative day (POD) and more than three quarter of patients on POD 2 (182/232, 77%). At the opposite, no patients of the control group were discharged on POD 2. Overall 30-day and 90-day morbidity and readmission rates were the same in both groups. There was no death in each group. CONCLUSIONS: This large case-matched study using a propensity score analysis suggests that implementation of ERAS program significantly reduced length of hospital stay without significant increases on overall morbidity, and readmission rates.

6.
J Am Soc Mass Spectrom ; 30(7): 1169-1173, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31066005

RESUMO

The aerosols present in the atmosphere of the Saturn's moon Titan are of particular planetary science interest and several spacecraft missions are already allowed to gather spectroscopic data. Titan haze's analogs, so-called tholins, were produced on earth to push forward the comprehension of their formation and properties. In this study, this highly complex mixture was analyzed here for the first time by trapped ion mobility spectrometry coupled to ultra-high resolution mass spectrometry (FTICR MS). Electrospray ionization revealed the characteristic CHNx-class components, with CHN5-6 and DBE 6-7 most abundant. Deploying specialized visualization, enabled by accurate mass measurements and elemental composition assignments, the adapted Kendrick mass defect analysis highlights the C2H3N homolog series, whereas the nitrogen-modified van Krevelen diagram exhibits a clear trend towards H/C 1.5 and N/C 0.5. More interestingly, the representation of m/z versus collision cross section (CCS) allowed hypothesizing a ramified N-PAH structural motif. State-of-the-art IMS is currently not able to resolve the isomeric continuum of ultra-complex mixtures; thus, peak parameters other than the CCS value are explored. As such, analyzing the mobility peak width versus m/z shows a linear increase in isomeric diversity between m/z 170 and 350 and a near plateau in diversity at higher m/z for the N-PAH-like structure. Due to the high complexity of the sample, these structural insights are only to be revealed by TIMS-FTICR MS.

7.
Obes Surg ; 29(3): 903-910, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30467707

RESUMO

OBJECTIVE: To evaluate the safety and efficacy of revisional Roux-en-Y gastric bypass (RYGB) after adjustable gastric banding (AGB) or sleeve gastrectomy (SG) compared with primary RYGB, in regard to early and late morbidity, weight, and resolution of obesity-related comorbidities. METHODS: The group of patients undergoing revisional RYGB was matched in a 1:1 ratio with control patient who underwent a primary RYGB, based on age, gender, American Society of Anesthesiologist (ASA) score, preoperative body mass index (BMI), and diabetes mellitus. Demographics, anthropometrics, preoperative work-up, and perioperative data were retrieved. RESULTS: One hundred fifteen patients (16 males and 99 females) with a mean age of 45.5 ± 1.5 years underwent revisional RYGB following either LAGB in 82 patients (71.3%) or laparoscopic sleeve gastrectomy (LSG) in 33 patients (28.7%). There was no conversion and no mortality in either group. Revisional RYGB was associated with similar early (16.5 vs 15.6%, ns) and late (42.6% vs 32.2%, ns) morbidity rates with a mean follow-up of 25.3 ± 16.6 months compared to primary laparoscopic Roux-en-Y gastric bypass. The revisional RYGB group had significantly less weight loss (mean %EWL 67.4 ± 20.7 vs 72.7 ± 22.9, p = 0.023 and mean %EBMI 68.1 ± 22 vs 78.3 ± 25.7, p = 0.01) at the time of 1 year. Improvement of comorbidities including hypertension (62.5 vs 70.5%; p > 0.05), diabetes (73.7 vs 79%; p > 0.05), and obstructive sleep apnea syndrome (100 vs 97%; p > 0.05) was similar. CONCLUSION: This large case-matched study suggests that conversion of SG or AGB to RYGB is feasible with early and late comparable morbidity in an accredited center; even weight results might be inferior.

8.
Atherosclerosis ; 275: 409-418, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29866392

RESUMO

BACKGROUND AND AIMS: LPCAT3 plays a major role in phospholipid metabolism in the liver and intestine. However, the impact of LPCAT3 on hematopoietic cell and macrophage functions has yet to be described. Our aim was to understand the functions of LPCAT3 in macrophages and to investigate whether LPCAT3 deficiency in hematopoietic cells may affect atherosclerosis development. METHODS: Mice with constitutive Lpcat3 deficiency (Lpcat3-/-) were generated. We used fetal hematopoietic liver cells to generate WT and Lpcat3-/- macrophages in vitro and to perform hematopoietic cell transplantation in recipient Ldlr-/- mice. RESULTS: Lpcat3-deficient macrophages displayed major reductions in the arachidonate content of phosphatidylcholines, phosphatidylethanolamines and, unexpectedly, plasmalogens. These changes were associated with altered cholesterol homeostasis, including an increase in the ratio of free to esterified cholesterol and a reduction in cholesterol efflux in Lpcat3-/- macrophages. This correlated with the inhibition of some LXR-regulated pathways, related to altered cellular availability of the arachidonic acid. Indeed, LPCAT3 deficiency was associated with decreased Abca1, Abcg1 and ApoE mRNA levels in fetal liver cells derived macrophages. In vivo, these changes translated into a significant increase in atherosclerotic lesions in Ldlr-/- mice with hematopoietic LPCAT3 deficiency. CONCLUSIONS: This study identifies LPCAT3 as a key factor in the control of phospholipid homeostasis and arachidonate availability in myeloid cells and underlines a new role for LPCAT3 in plasmalogen metabolism. Moreover, our work strengthens the link between phospholipid and sterol metabolism in hematopoietic cells, with significant consequences on nuclear receptor-regulated pathways and atherosclerosis development.


Assuntos
1-Acilglicerofosfocolina O-Aciltransferase/deficiência , Aterosclerose/enzimologia , Colesterol/metabolismo , Células-Tronco Hematopoéticas/enzimologia , Macrófagos/enzimologia , Fosfolipídeos/metabolismo , Placa Aterosclerótica , 1-Acilglicerofosfocolina O-Aciltransferase/genética , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Ácido Araquidônico/metabolismo , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Modelos Animais de Doenças , Predisposição Genética para Doença , Transplante de Células-Tronco Hematopoéticas , Receptores X do Fígado/metabolismo , Macrófagos/transplante , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptores de LDL/deficiência , Receptores de LDL/genética
10.
Sci Rep ; 7(1): 3053, 2017 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-28596518

RESUMO

Although plasma phospholipid transfer protein (PLTP) has been mainly studied in the context of atherosclerosis, it shares homology with proteins involved in innate immunity. Here, we produced active recombinant human PLTP (rhPLTP) in the milk of new lines of transgenic rabbits. We successfully used rhPLTP as an exogenous therapeutic protein to treat endotoxemia and sepsis. In mouse models with injections of purified lipopolysaccharides or with polymicrobial infection, we demonstrated that rhPLTP prevented bacterial growth and detoxified LPS. In further support of the antimicrobial effect of PLTP, PLTP-knocked out mice were found to be less able than wild-type mice to fight against sepsis. To our knowledge, the production of rhPLTP to counter infection and to reduce endotoxemia and its harmful consequences is reported here for the first time. This paves the way for a novel strategy to satisfy long-felt, but unmet needs to prevent and treat sepsis.


Assuntos
Anti-Infecciosos/uso terapêutico , Proteínas de Transferência de Fosfolipídeos/uso terapêutico , Sepse/tratamento farmacológico , Animais , Anti-Infecciosos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Transferência de Fosfolipídeos/farmacologia , Coelhos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
11.
Front Neurosci ; 11: 245, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28515677

RESUMO

The polysialic acid (PSA) is a large glycan that is added to cell-surface proteins during their post-translational maturation. In the brain, PSA modulates distances between cells and controls the plasticity of the nervous system. In the hypothalamus, PSA is involved in many aspects of energy balance including food intake, osmoregulation, circadian rhythm, and sleep. In this work, we investigated the role of hypothalamic PSA in the regulation of plasma cholesterol levels and distribution. We report that HFD consumption in mice rapidly increased plasma cholesterol, including VLDL, LDL, and HDL-cholesterol. Although plasma VLDL-cholesterol was normalized within the first week, LDL and HDL were still elevated after 2 weeks upon HFD. Importantly, we found that hypothalamic PSA removal aggravated LDL elevation and reduced HDL levels upon HFD. These results indicate that hypothalamic PSA controls plasma lipoprotein profile by circumventing the rise of LDL-to-HDL cholesterol ratio in plasma during overfeeding. Although mechanisms by which hypothalamic PSA controls plasma cholesterol homeostasis remains to be elucidated, these findings also suggest that low level of hypothalamic PSA might be a risk factor for dyslipidemia and cardiovascular diseases.

12.
Obes Surg ; 27(10): 2590-2598, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28429171

RESUMO

BACKGROUND: Increased lipopolysaccharide (LPS) translocation due to altered intestinal permeability has been suggested as a mechanism for obesity-associated insulin resistance. The goal of this study was to assess the effect of sleeve gastrectomy (SG) on intestinal barrier permeability in diet-induced obese mice. MATERIALS AND METHODS: Four weeks after surgery, the effects of SG on intestinal permeabilities were assessed ex vivo and in vivo in male C57Bl/6J mice fed a high-fat diet. Gene expression of tight junction proteins and inflammatory cytokines was measured in jejunum, colon, liver, and inguinal adipose tissue. Plasma LPS was quantified by HPLCMS/MS spectrometry. RESULTS: SG significantly reduced body weight and improved glucose homeostasis, as expected. SG decreased paracellular (p = 0.01) and transcellular permeability (p = 0.03) in the jejunum; and increased mRNA levels of the tight junction proteins Jam A (p = 0.02) and occludin (p = 0.01). In contrast in the distal colon, paracellular permeability tended to be increased (p = 0.07) while transcellular permeability was significantly induced (p = 0.03) after SG. In vivo, the paracellular permeability was significantly increased 3 weeks after SG (p = 0.02). Plasma LPS level were increased after SG (p = 0.03), as well as mRNA levels of adipose and hepatic inflammatory markers (p = 0.02). CONCLUSIONS: SG significantly modifies intestinal permeability in a differential manner between the proximal and distal intestine. These changes promote LPS translocation in plasma, induce a low-grade pro-inflammatory state in adipose tissue and liver, but do not impair the SG-induced glucose homeostasis improvement.


Assuntos
Dieta Hiperlipídica , Mucosa Intestinal/metabolismo , Obesidade/cirurgia , Tecido Adiposo/metabolismo , Adiposidade , Animais , Gastrectomia/métodos , Resistência à Insulina , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Permeabilidade
13.
Sci Rep ; 7: 41481, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28148911

RESUMO

Atherosclerotic cardiovascular disease (CVD) represents the largest cause of mortality in end-stage renal disease (ESRD). CVD in ESRD is not explained by classical CVD risk factors such as HDL cholesterol mass levels making functional alterations of lipoproteins conceivable. HDL functions in atheroprotection by promoting reverse cholesterol transport (RCT), comprising cholesterol efflux from macrophage foam cells, uptake into hepatocytes and final excretion into the feces. ESRD-HDL (n = 15) were compared to healthy control HDL (n = 15) for their capacity to promote in vitro (i) cholesterol efflux from THP-1 macrophage foam cells and (ii) SR-BI-mediated selective uptake into ldla[SR-BI] cells as well as (iii) in vivo RCT. Compared with HDL from controls, ESRD-HDL displayed a significant reduction in mediating cholesterol efflux (p < 0.001) and SR-BI-mediated selective uptake (p < 0.01), two key steps in RCT. Consistently, also the in vivo capacity of ESRD-HDL to promote RCT when infused into wild-type mice was significantly impaired (p < 0.01). In vitro oxidation of HDL from healthy controls with hypochloric acid was able to fully mimic the impaired biological activities of ESRD-HDL. In conclusion, we demonstrate that HDL from ESRD patients is dysfunctional in key steps as well as overall RCT, likely due to oxidative modification.


Assuntos
Colesterol/metabolismo , Falência Renal Crônica/metabolismo , Lipoproteínas HDL/metabolismo , Animais , Transporte Biológico , Humanos , Camundongos Endogâmicos C57BL , Oxirredução
14.
Microbiol Res ; 192: 172-184, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27664735

RESUMO

The antagonistic activity of 46 bacterial strains isolated from Bordeaux vineyards were evaluated against Phaeomoniella chlamydospora, a major grapevine pathogen involved in Esca. The reduction of the necrosis length of stem cuttings ranged between 31.4% and 38.7% for the 8 most efficient strains. Two in planta trials allowed the selection of the two best strains, Bacillus pumilus (S32) and Paenibacillus sp. (S19). Their efficacy was not dependent on application method; co-inoculation, prevention in the wood and soil inoculation were tested. The involvement of antibiosis by the secretion of diffusible and/or volatile compounds in the antagonistic capacity of these two strains was assessed in vitro. Volatile compounds secreted by B. pumilus (S32) and Paenibacillus sp. (S19) were identified by gas chromatography/mass spectroscopy (GC/MS). The volatile compounds 1-octen-3-ol and 2,5-dimethyl pyrazine were obtained commercially and tested, and they showed strong antifungal activity against P. chlamydospora, which suggested that these compounds may play an important role in the bacterial antagonistic activity in planta. Furthermore, the expression of 10 major grapevine defense genes was quantified by real-time polymerase chain reaction, which demonstrated that the two strains significantly affected the grapevine transcripts four days after their application on the plants. High expression levels of different genes associated with P. chlamydospora infection in B. pumilus pre-treated plants suggests that this strain induces systemic resistance in grapevine. For the first time, we demonstrated the ability of two bacterial strains, B. pumilus and Paenibacillus sp., isolated from grapevine wood, to control P. chlamydospora via direct and/or indirect mechanisms.


Assuntos
Antibiose , Ascomicetos/fisiologia , Bactérias/classificação , Fenômenos Fisiológicos Bacterianos , Doenças das Plantas/microbiologia , Vitis/microbiologia , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Ascomicetos/efeitos dos fármacos , Bactérias/genética , Bactérias/metabolismo , Testes de Sensibilidade Microbiana , Fenótipo , Compostos Orgânicos Voláteis/metabolismo , Compostos Orgânicos Voláteis/farmacologia
15.
J Phys Chem A ; 120(33): 6529-40, 2016 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-27471793

RESUMO

The chemical composition of Titan organic haze is poorly known. To address this issue, laboratory analogues named tholins are synthesized and analyzed by methods often requiring an extraction process in a carrier solvent. These methods exclude the analysis of the insoluble tholins' fraction and assume a hypothetical chemical equivalence between soluble and insoluble fractions. In this work, we present a powerful complementary analysis method recently developed on the DESIRS VUV synchrotron beamline at SOLEIL. It involves soft pyrolysis of tholins at ∼230 °C and electron/ion coincidence analysis of the emitted volatile compounds photoionized by tunable synchrotron radiation. By comparison with reference photoelectron spectra (PES), the spectral information collected on the detected molecules yields their isomeric structure. The method is more readily applied to light species (m/z ≤ 69), while for heavier ones, the number of possibilities and the lack of PES reference spectra in the literature limit its analysis. A notable pattern in the analyzed tholins is the presence of species containing adjacent doubly bonded N atoms, which might be a signature of heterogeneous incorporation of N2 in tholins.

16.
Reprod Biol Endocrinol ; 14(1): 28, 2016 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-27209151

RESUMO

BACKGROUND: Follicular fluid (FF) is an important micro-environment influencing oocyte growth, its development competence, and embryo viability. The FF content analysis allows to identify new relevant biomarkers, which could be predictive of in vitro fertilization (IVF) outcomes. Inside ovarian follicle, the amount of FF components from granulosa cells (GC) secretion, could be regulated by gonadotropins, which play a major role in follicle development. METHODS: This prospective study included 61 female undergoing IVF or Intra-cytoplasmic sperm injection (ICSI) procedure. Apolipoprotein B (APOB) concentrations in follicular fluid and APOB gene and protein expression in granulosa cells from reproductively aged women undergoing an in vitro fertilization program were measured. The statistical analyses were performed according to a quartile model based on the amount of APOB level found in FF. RESULTS: Amounts of APOB were detected in human FF samples (mean ± SD: 244.6 ± 185.9 ng/ml). The odds of obtaining an oocyte in the follicle and a fertilized oocyte increased significantly when APOB level in FF was higher than 112 ng/ml [i.e., including in Quartile Q 2, Q3 and Q4] (p = 0.001; p < 0.001, respectively). The probabilities of obtaining an embryo and a top quality embryo on day 2, were significantly higher if APOB levels were within the ranges of 112 and 330 ng/ml (i.e. in Q2 and Q3) or 112 and 230 ng/ml (i.e. in Q2), respectively (p < 0.001; p = 0.047, respectively). In addition, our experiments in vitro indicated that APOB gene and protein expression, along with APOB content into culture were significantly under-expressed in GC upon stimulation with gonadotropins (follicular stimulating hormone: FSH and/or human chorionic gonadotropin: hCG). CONCLUSION: We are reporting a positive and statistically significant associations between APOB and oocyte retrieval, oocyte fertilization, and embryo quality. Using an experimental study component, the authors report significant reduced APOB expression and content for luteinized granulosa cells cultured in the presence of gonadotropins.


Assuntos
Apolipoproteínas B/metabolismo , Gonadotropina Coriônica/uso terapêutico , Fertilização In Vitro , Hormônio Foliculoestimulante/uso terapêutico , Líquido Folicular/metabolismo , Adulto , Biomarcadores/metabolismo , Embrião de Mamíferos , Desenvolvimento Embrionário , Feminino , Fertilização , Células da Granulosa/metabolismo , Humanos , Recuperação de Oócitos , Indução da Ovulação , Estudos Prospectivos , Resultado do Tratamento
17.
Expert Opin Ther Targets ; 20(1): 47-59, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26212254

RESUMO

INTRODUCTION: Over recent decades, attempts to ascertain the pro-atherogenic nature of plasma cholesteryl ester transfer protein (CETP) and to establish the relevance of its pharmacological blockade as a promising high density lipoproteins-raising and anti-atherogenic therapy have been disappointing. AREAS COVERED: The current review focuses on CETP as a multifaceted protein, on genetic variations at the CETP gene and on their possible consequences for cardiovascular risk in human populations. Specific attention is given to physiological modulation of endogenous CETP activity by the apoC1 inhibitor. Finally, the rationale behind the need for selection of patients to treat is discussed in the light of recent studies. EXPERT OPINION: At this stage one can only speculate on the clinical outcome of pharmacological CETP inhibitors in high-risk populations, but recent advances give cause to adjust the expectations from now on. The CETP effect is probably largely influenced by the overall metabolic state, and whether CETP blockade may be relevant or not in promoting cholesterol disposal is still questioned. The possible need for a careful stratification of patients to treat with CETP inhibitors is outlined. Finally, manipulation of CETP activity should be considered with caution in the context of sepsis and infectious diseases.


Assuntos
Aterosclerose/prevenção & controle , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Aterosclerose/etiologia , Aterosclerose/genética , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Proteínas de Transferência de Ésteres de Colesterol/genética , Desenho de Fármacos , Humanos , Terapia de Alvo Molecular , Seleção de Pacientes , Fatores de Risco
18.
Hum Mol Genet ; 24(23): 6603-13, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26358774

RESUMO

Cohen Syndrome (CS) is a rare autosomal recessive disorder, with defective glycosylation secondary to mutations in the VPS13B gene, which encodes a protein of the Golgi apparatus. Besides congenital neutropenia, retinopathy and intellectual deficiency, CS patients are faced with truncal obesity. Metabolism investigations showed abnormal glucose tolerance tests and low HDL values in some patients, and these could be risk factors for the development of diabetes mellitus and/or cardiovascular complications. To understand the mechanisms involved in CS fat storage, we used two models of adipogenesis differentiation: (i) SGBS pre-adipocytes with VPS13B invalidation thanks to siRNA delivery and (ii) CS primary fibroblasts. In both models, VPS13B invalidation led to accelerated differentiation into fat cells, which was confirmed by the earlier and increased expression of specific adipogenic genes, consequent to the increased response of cells to insulin stimulation. At the end of the differentiation protocol, these fat cells exhibited decreased AKT2 phosphorylation after insulin stimulation, which suggests insulin resistance. This study, in association with the in-depth analysis of the metabolic status of the patients, thus allowed us to recommend appropriate nutritional education to prevent the occurrence of diabetes mellitus and to put forward recommendations for the follow-up of CS patients, in particular with regard to the development of metabolic syndrome. We also suggest replacing the term obesity by abnormal fat distribution in CS, which should reduce the number of inappropriate diagnoses in patients who are referred only on the basis of intellectual deficiency associated with obesity.


Assuntos
Adipogenia , Distribuição da Gordura Corporal , Diabetes Mellitus Tipo 2/fisiopatologia , Dedos/anormalidades , Insulina/fisiologia , Deficiência Intelectual/fisiopatologia , Microcefalia/fisiopatologia , Hipotonia Muscular/fisiopatologia , Miopia/fisiopatologia , Obesidade/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/fisiopatologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Feminino , Dedos/fisiopatologia , Humanos , Deficiência Intelectual/complicações , Masculino , Microcefalia/complicações , Pessoa de Meia-Idade , Modelos Biológicos , Hipotonia Muscular/complicações , Mutação , Miopia/complicações , Obesidade/complicações , Degeneração Retiniana , Risco , Transdução de Sinais , Proteínas de Transporte Vesicular/genética , Adulto Jovem
19.
Science ; 349(6247): aab0689, 2015 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-26228156

RESUMO

Comets harbor the most pristine material in our solar system in the form of ice, dust, silicates, and refractory organic material with some interstellar heritage. The evolved gas analyzer Cometary Sampling and Composition (COSAC) experiment aboard Rosetta's Philae lander was designed for in situ analysis of organic molecules on comet 67P/Churyumov-Gerasimenko. Twenty-five minutes after Philae's initial comet touchdown, the COSAC mass spectrometer took a spectrum in sniffing mode, which displayed a suite of 16 organic compounds, including many nitrogen-bearing species but no sulfur-bearing species, and four compounds­methyl isocyanate, acetone, propionaldehyde, and acetamide­that had not previously been reported in comets.

20.
J Lipid Res ; 56(7): 1363-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26023073

RESUMO

Quantitation of plasma lipopolysaccharides (LPSs) might be used to document Gram-negative bacterial infection. In the present work, LPS-derived 3-hydroxymyristate was extracted from plasma samples with an organic solvent, separated by reversed phase HPLC, and quantitated by MS/MS. This mass assay was combined with the limulus amebocyte lysate (LAL) bioassay to monitor neutralization of LPS activity in biological samples. The described HPLC/MS/MS method is a reliable, practical, accurate, and sensitive tool to quantitate LPS. The combination of the LAL and HPLC/MS/MS analyses provided new evidence for the intrinsic capacity of plasma lipoproteins and phospholipid transfer protein to neutralize the activity of LPS. In a subset of patients with systemic inflammatory response syndrome, with documented infection but with a negative plasma LAL test, significant amounts of LPS were measured by the HPLC/MS/MS method. Patients with the highest plasma LPS concentration were more severely ill. HPLC/MS/MS is a relevant method to quantitate endotoxin in a sample, to assess the efficacy of LPS neutralization, and to evaluate the proinflammatory potential of LPS in vivo.


Assuntos
Análise Química do Sangue/métodos , Caranguejos Ferradura , Lipopolissacarídeos/sangue , Proteínas de Membrana/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Lipopolissacarídeos/química , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem
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