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1.
Microb Pathog ; 195: 106909, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39218373

RESUMO

Brucellosis is a zoonotic disease caused by Brucella, which is difficult to eliminate by conventional drugs. Therefore, a novel multi-epitope vaccine (MEV) was designed to prevent human Brucella infection. Based on the method of "reverse vaccinology", cytotoxic T lymphocyte epitopes (CTLEs), helper T lymphocyte epitopes (HTLEs), linear B-cell epitopes (LBEs) and conformational B-cell epitopes (CBEs) of four Brucella proteins (VirB9, VirB10, Omp 19 and Omp 25) were obtained. In order to keep the correct protein folding, the multiple epitopes was constructed by connecting epitopes through linkers. In view of the significant connection between human leukocyte antigen CTLA-4 and B7 molecules found on antigen presenting cells (APCs), a new vaccine (V_C4MEV) for preventing brucellosis was created by combining CTLA-4 immunoglobulin variable region (IgV_CTLA-4) with MEV protein. Immunoinformatics analysis showed that V_C4MEV has a good secondary and tertiary structure. Additionally, molecular docking and molecular dynamics simulation (MD) revealed a robust binding affinity between IgV_ CTLA-4 and the B7 molecule. Notably, the vaccine V_C4MEV was demonstrated favorable immunogenicity and antigenicity in both in vitro and in vivo experiments. V_C4MEV had the potential to activate defensive cells and immune responses, offering a hopeful approach for developing vaccines against Brucella in the upcoming years.


Assuntos
Vacina contra Brucelose , Brucella , Brucelose , Antígeno CTLA-4 , Biologia Computacional , Epitopos de Linfócito B , Epitopos de Linfócito T , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Brucelose/prevenção & controle , Brucelose/imunologia , Epitopos de Linfócito B/imunologia , Antígeno CTLA-4/imunologia , Epitopos de Linfócito T/imunologia , Vacina contra Brucelose/imunologia , Animais , Humanos , Brucella/imunologia , Brucella/genética , Camundongos , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/química , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas da Membrana Bacteriana Externa/genética , Imunoinformática , Lipoproteínas
2.
Vaccine ; 42(24): 126266, 2024 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-39232399

RESUMO

Tuberculosis (TB) is one of the leading causes of death from infectious diseases, killing approximately 1.3 million people worldwide in 2022 alone. The current vaccine for TB contains a live attenuated bacterium, Mycobacterium bovis BCG (Bacille Calmette-Guérin). The BCG vaccine is highly effective in preventing severe forms of childhood TB but does not protect against latent infection or disease in older age groups. A new or improved BCG vaccine for prevention of pulmonary TB is urgently needed. In this study, we infected murine bone marrow derived dendritic cells from C57BL/6 mice with M. bovis BCG followed by elution and identification of BCG-derived MHC class I and class II-bound peptides using tandem mass spectrometry. We identified 1436 MHC-bound peptides of which 94 were derived from BCG. Fifty-five peptides were derived from MHC class I molecules and 39 from class II molecules. We tested the 94 peptides for their immunogenicity using IFN- γ ELISPOT assay with splenocytes purified from BCG immunized mice and 10 showed positive responses. Seven peptides were derived from MHC II and three from MHC class I. In particular, MHC class II binding peptides derived from the mycobacterial surface lipoprotein Mpt83 were highly antigenic. Further evaluations of these immunogenic BCG peptides may identify proteins useful as new TB vaccine candidates.


Assuntos
Antígenos de Bactérias , Vacina BCG , Proteínas de Bactérias , Células Dendríticas , Camundongos Endogâmicos C57BL , Mycobacterium bovis , Animais , Antígenos de Bactérias/imunologia , Mycobacterium bovis/imunologia , Camundongos , Vacina BCG/imunologia , Proteínas de Bactérias/imunologia , Células Dendríticas/imunologia , Desenvolvimento de Vacinas , Feminino , Proteômica/métodos , Linfócitos T/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Lipoproteínas/imunologia , Tuberculose/prevenção & controle , Tuberculose/imunologia , Peptídeos/imunologia , Proteínas de Membrana
3.
Cells ; 13(17)2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39273010

RESUMO

Helicobacter pylori is a bacterial pathogen that colonizes the human stomach, where it can cause a variety of diseases. H. pylori uses a cluster of sheathed flagella for motility, which is required for host colonization in animal models. The flagellar sheath is continuous with the outer membrane and is found in most Helicobacter species identified to date. HP0018 is a predicted lipoprotein of unknown function that is conserved in Helicobacter species that have flagellar sheaths but is absent in Helicobacter species that have sheath-less flagella. Deletion of hp0018 in H. pylori B128 resulted in the formation of long chains of outer membrane vesicles, which were most evident in an aflagellated variant of the Δhp0018 mutant that had a frameshift mutation in fliP. Flagellated cells of the Δhp0018 mutant possessed what appeared to be a normal flagellar sheath, suggesting that HP0018 is not required for sheath formation. Cells of the Δhp0018 mutant were also less helical in shape compared to wild-type cells. A HP0018-superfolder green fluorescent fusion protein expressed in the H. pylori Δhp0018 mutant formed fluorescent foci at the cell poles and lateral sites. Co-immunoprecipitation assays with HP0018 identified two enzymes involved in the modification of the cell wall peptidoglycan, AmiA and MltD, as potential HP0018 interaction partners. HP0018 may modulate the activity of AmiA or MltD, and in the absence of HP0018, the unregulated activity of these enzymes may alter the peptidoglycan layer in a manner that results in an altered cell shape and hypervesiculation.


Assuntos
Flagelos , Helicobacter pylori , Helicobacter pylori/genética , Helicobacter pylori/metabolismo , Helicobacter pylori/fisiologia , Flagelos/metabolismo , Membrana Celular/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Humanos , Lipoproteínas/metabolismo , Lipoproteínas/genética
4.
J Appl Lab Med ; 9(5): 1040-1056, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39225455

RESUMO

BACKGROUND: The accurate measurement of blood lipids and lipoproteins is crucial for the clinical management of atherosclerotic disease risk. Despite progress in standardization, there are still significant variations in pre-analytical requirements, methods, nomenclature, and reporting work flows. CONTENT: The guidance document aims to improve standardization of clinical lipid testing work flows. It provides recommendations for the components of the lipid panel, fasting requirements, reporting of results, and specific recommendations for non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], apolipoprotein B (apo B), point-of-care lipid testing, and LDL subfraction testing. SUMMARY: Lipid panels should always report non-HDL-C and LDL-C calculations if possible. Fasting is not routinely required except in specific cases. Modern equations should be utilized for LDL-C calculation. These equations allow for LDL-C reporting at elevated concentrations of triglycerides and obviate the need for direct measured LDL-C in most cases.


Assuntos
Lipídeos , Lipoproteínas , Humanos , Lipoproteínas/sangue , Lipoproteínas/análise , Lipídeos/sangue , Lipídeos/análise , LDL-Colesterol/sangue , Apolipoproteínas B/sangue , Aterosclerose/sangue , Aterosclerose/diagnóstico , Lipoproteína(a)/sangue
5.
Nat Commun ; 15(1): 7616, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39223154

RESUMO

Curved cell shapes are widespread among bacteria and important for cellular motility, virulence and fitness. However, the underlying morphogenetic mechanisms are still incompletely understood. Here, we identify an outer-membrane protein complex that promotes cell curvature in the photosynthetic species Rhodospirillum rubrum. We show that the R. rubrum porins Por39 and Por41 form a helical ribbon-like structure at the outer curve of the cell that recruits the peptidoglycan-binding lipoprotein PapS, with PapS inactivation, porin delocalization or disruption of the porin-PapS interface resulting in cell straightening. We further demonstrate that porin-PapS assemblies act as molecular cages that entrap the cell elongation machinery, thus biasing cell growth towards the outer curve. These findings reveal a mechanistically distinct morphogenetic module mediating bacterial cell shape. Moreover, they uncover an unprecedented role of outer-membrane protein patterning in the spatial control of intracellular processes, adding an important facet to the repertoire of regulatory mechanisms in bacterial cell biology.


Assuntos
Lipoproteínas , Porinas , Rhodospirillum rubrum , Porinas/metabolismo , Porinas/genética , Rhodospirillum rubrum/metabolismo , Lipoproteínas/metabolismo , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas da Membrana Bacteriana Externa/genética
6.
ACS Infect Dis ; 10(9): 3256-3272, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39231002

RESUMO

The survival and proliferation of pathogenic Leptospira within a host are complex phenomena that require careful consideration. The ErpY-like lipoprotein, found on the outer membrane surface of Leptospira, plays a crucial role in enhancing the bacterium's pathogenicity. The rErpY-like protein, in its recombinant form, contributes significantly to spirochete virulence by interacting with various host factors, including host complement regulators. This interaction facilitates the bacterium's evasion of the host complement system, thereby augmenting its overall pathogenicity. The rErpY-like protein exhibits a robust binding affinity to soluble fibrinogen, a vital component of the host coagulation system. In this study, we demonstrate that the rErpY-like protein intervenes in the clotting process of the platelet-poor citrated plasma of bovines and humans in a concentration-dependent manner. It significantly reduces clot density, alters the viscoelastic properties of the clot, and diminishes the average clotting rate in plasma. Furthermore, the ErpY-like protein inhibits thrombin-catalyzed fibrin formation in a dose-dependent manner and exhibits saturable binding to thrombin, suggesting its significant role in leptospiral infection. These findings provide compelling evidence for the anticoagulant effect of the ErpY-like lipoprotein and its significant role in leptospiral infection.


Assuntos
Coagulação Sanguínea , Fibrinogênio , Trombina , Fibrinogênio/metabolismo , Fibrinogênio/química , Humanos , Trombina/metabolismo , Animais , Bovinos , Ligação Proteica , Leptospira/metabolismo , Leptospirose/microbiologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Lipoproteínas/metabolismo , Interações Hospedeiro-Patógeno
7.
Microb Pathog ; 195: 106872, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39173852

RESUMO

Membrane lipoproteins serve as primary pro-inflammatory virulence factors in Mycoplasma genitalium. Membrane lipoproteins primarily induce inflammatory responses by activating Toll-like Receptor 2 (TLR2); however, the role of the metabolic status of urethral epithelial cells in inflammatory response remains unclear. In this study, we found that treatment of uroepithelial cell lines with M. genitalium membrane lipoprotein induced metabolic reprogramming, characterized by increased aerobic glycolysis, decreased oxidative phosphorylation, and increased production of the metabolic intermediates acetyl-CoA and malonyl-CoA. The metabolic shift induced by membrane lipoproteins is reversible upon blocking MyD88 and TRAM. Malonyl-CoA induces malonylation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and malonylated GAPDH could dissociate from the 3' untranslated region of TNF-α and IFN-γ mRNA. This dissociation greatly reduces the inhibitory effect on the translation of TNF-α and IFN-γ mRNA, thus achieving fine-tuning control over cytokine secretion. These findings suggest that GAPDH malonylation following M. genitalium infection is an important inflammatory signal that plays a crucial role in urogenital inflammatory diseases.


Assuntos
Citocinas , Células Epiteliais , Interferon gama , Mycoplasma genitalium , Fator de Necrose Tumoral alfa , Mycoplasma genitalium/metabolismo , Mycoplasma genitalium/genética , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Humanos , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interferon gama/metabolismo , Linhagem Celular , Lipoproteínas/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/genética , Uretra/microbiologia , Uretra/metabolismo , Infecções por Mycoplasma/metabolismo , Infecções por Mycoplasma/microbiologia , Fatores de Virulência/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Glicólise , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética
8.
Curr Opin Lipidol ; 35(5): 248-252, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39172716

RESUMO

PURPOSE OF REVIEW: This review examines the evolving role of the fat-inducing transcript 2 (FIT2) protein in lipid droplet (LD) biology and its broader implications in cellular physiology and disease. With recent advancements in understanding FIT2 function across various model systems, this review provides a timely synthesis of its mechanisms and physiological significance. RECENT FINDINGS: FIT2, an endoplasmic reticulum (ER)-resident protein, has been established as a critical regulator of LD formation in diverse organisms, from yeast to mammals. It facilitates LD biogenesis by sequestering diacylglycerol (DAG) and potentially influencing ER membrane dynamics. Beyond its role in lipid metabolism, FIT2 intersects with the ER-associated degradation (ERAD), is critical for protein homeostasis, and is linked to the unfolded protein response (UPR). Dysregulation of FIT2 has also been linked to metabolic disorders such as insulin resistance and lipodystrophy, highlighting its clinical relevance. SUMMARY: Insights into FIT2 function underscore its pivotal role in LD formation and lipid homeostasis. Understanding its involvement in ER proteostasis and very low density lipoprotein biogenesis has broad implications for metabolic diseases and cancer. Therapeutic strategies targeting FIT2 may offer novel approaches to modulate lipid metabolism and mitigate associated pathologies. Further research is needed to elucidate the full spectrum of FIT2's interactions within cellular lipid and protein networks, potentially uncovering new therapeutic avenues for metabolic and ER stress-related disorders.


Assuntos
Retículo Endoplasmático , Proteostase , Humanos , Retículo Endoplasmático/metabolismo , Animais , Lipoproteínas/metabolismo , Lipoproteínas/genética , Gotículas Lipídicas/metabolismo , Resposta a Proteínas não Dobradas , Metabolismo dos Lipídeos/genética , Proteínas de Membrana
9.
mBio ; 15(9): e0174924, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39145656

RESUMO

Lyme disease, caused by spirochetes in the Borrelia burgdorferi sensu lato clade within the Borrelia genus, is transmitted by Ixodes ticks and is currently the most prevalent and rapidly expanding tick-borne disease in Europe and North America. We report complete genome sequences of 47 isolates that encompass all established species in this clade while highlighting the diversity of the widespread human pathogenic species B. burgdorferi. A similar set of plasmids has been maintained throughout Borrelia divergence, indicating that they are a key adaptive feature of this genus. Phylogenetic reconstruction of all sequenced Borrelia genomes revealed the original divergence of Eurasian and North American lineages and subsequent dispersals that introduced B. garinii, B. bavariensis, B. lusitaniae, B. valaisiana, and B. afzelii from East Asia to Europe and B. burgdorferi and B. finlandensis from North America to Europe. Molecular phylogenies of the universally present core replicons (chromosome and cp26 and lp54 plasmids) are highly consistent, revealing a strong clonal structure. Nonetheless, numerous inconsistencies between the genome and gene phylogenies indicate species dispersal, genetic exchanges, and rapid sequence evolution at plasmid-borne loci, including key host-interacting lipoprotein genes. While localized recombination occurs uniformly on the main chromosome at a rate comparable to mutation, lipoprotein-encoding loci are recombination hotspots on the plasmids, suggesting adaptive maintenance of recombinant alleles at loci directly interacting with the host. We conclude that within- and between-species recombination facilitates adaptive sequence evolution of host-interacting lipoprotein loci and contributes to human virulence despite a genome-wide clonal structure of its natural populations. IMPORTANCE: Lyme disease (also called Lyme borreliosis in Europe), a condition caused by spirochete bacteria of the genus Borrelia, transmitted by hard-bodied Ixodes ticks, is currently the most prevalent and rapidly expanding tick-borne disease in the United States and Europe. Borrelia interspecies and intraspecies genome comparisons of Lyme disease-related bacteria are essential to reconstruct their evolutionary origins, track epidemiological spread, identify molecular mechanisms of human pathogenicity, and design molecular and ecological approaches to disease prevention, diagnosis, and treatment. These Lyme disease-associated bacteria harbor complex genomes that encode many genes that do not have homologs in other organisms and are distributed across multiple linear and circular plasmids. The functional significance of most of the plasmid-borne genes and the multipartite genome organization itself remains unknown. Here we sequenced, assembled, and analyzed whole genomes of 47 Borrelia isolates from around the world, including multiple isolates of the human pathogenic species. Our analysis elucidates the evolutionary origins, historical migration, and sources of genomic variability of these clinically important pathogens. We have developed web-based software tools (BorreliaBase.org) to facilitate dissemination and continued comparative analysis of Borrelia genomes to identify determinants of human pathogenicity.


Assuntos
Genoma Bacteriano , Lipoproteínas , Doença de Lyme , Filogenia , Recombinação Genética , Seleção Genética , Doença de Lyme/microbiologia , Doença de Lyme/transmissão , Lipoproteínas/genética , Humanos , América do Norte , Variação Genética , Borrelia burgdorferi/genética , Borrelia burgdorferi/classificação , Europa (Continente) , Plasmídeos/genética , Ixodes/microbiologia , Borrelia/genética , Borrelia/classificação , Evolução Molecular , Sequenciamento Completo do Genoma , Animais , Interações entre Hospedeiro e Microrganismos/genética , Grupo Borrelia Burgdorferi/genética , Grupo Borrelia Burgdorferi/classificação
10.
Nutrients ; 16(15)2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39125409

RESUMO

Cardiovascular diseases (CVDs) represent the leading cause of mortality worldwide, despite the significant advancements that have been made in terms of primary and secondary prevention strategies over the past decades [...].


Assuntos
Doenças Cardiovasculares , Lipoproteínas , Humanos , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/etiologia , Lipoproteínas/sangue , Estado Nutricional
11.
Int J Mol Sci ; 25(15)2024 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-39125855

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by the build-up of fat in the liver of individuals in the absence of alcohol consumption. This condition has become a burden in modern societies aggravated by the lack of appropriate predictive biomarkers (other than liver biopsy). To better understand this disease and to find appropriate biomarkers, a new technology has emerged in the last two decades with the ability to explore the unmapped role of lipids in this disease: lipidomics. This technology, based on the combination of chromatography and mass spectrometry, has been extensively used to explore the lipid metabolism of NAFLD. In this review, we aim to summarize the knowledge gained through lipidomics assays exploring tissues, plasma, and lipoproteins from individuals with NAFLD. Our goal is to identify common features and active pathways that could facilitate the finding of a reliable biomarker from this field. The most frequent observation was a variable decrease (1-9%) in polyunsaturated fatty acids in phospholipids and non-esterified fatty acids in NAFLD patients, both in plasma and liver. Additionally, a reduction in phosphatidylcholines is a common feature in the liver. Due to the scarcity of studies, further research is needed to properly detect lipoprotein, plasma, and tissue lipid signatures of NAFLD etiologies, and NAFLD subtypes, and to define the relevance of this technology in disease management strategies in the push toward personalized medicine.


Assuntos
Biomarcadores , Lipidômica , Hepatopatia Gordurosa não Alcoólica , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Humanos , Biomarcadores/sangue , Lipidômica/métodos , Lipoproteínas/metabolismo , Lipoproteínas/sangue , Metabolismo dos Lipídeos , Fígado/metabolismo , Animais
12.
Sci Rep ; 14(1): 18098, 2024 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-39103476

RESUMO

Despite the clear association between remnant cholesterol (RC)and diabetes risk, no study to date has examined the relationship between RC and reversal of prediabetes to normoglycemia. This retrospective cohort study included a total of 15,023 patients with prediabetes who underwent a physical examination between 2010 and 2016. The link between initial RC levels and the reversion from prediabetes to normoglycemia was analyzed using the Cox proportional-hazards regression model. Additionally, the study explored the possible relationship between RC and the probability of returning normoglycemia by applying Cox proportional hazards regression models with cubic spline functions. To address competing risks, a multivariate Cox regression analysis was undertaken, treating the onset of diabetes as a competing risk event for reversing prediabetes to normoglycemia. Additionally, the study incorporated extensive subgroup analyses alongside multiple sensitivity analyses, enhancing the reliability and robustness of the results. After adjusting for covariates, the findings indicated that RC was inversely associated with the likelihood of reverting to normoglycemia (per 5 mg/dL increase, HR = 0.918, 95% CI 0.909-0.927). The analysis also revealed a nonlinear relationship between RC and normoglycemia reversion, with an inflection point at 51.08 mg/dL. For RC values below this inflection point (RC < 50.08 mg/dL), the HR for the probability of returning to normoglycemia was 0.907 (95% CI 0.897-0.917 per 5 mg/dL). Additionally, the competing risks model demonstrated a negative relationship between RC and the reversal of prediabetes to normoglycemia (SHR = 0.92, 95% CI 0.91-0.93). Sensitivity analyses confirmed the robustness and stability of these results. This study demonstrated a negative and non-linear association between RC and the probability of reversion to normoglycemia in Chinese adults with prediabetes. By actively intervening to reduce RC levels, at least to below 51.08 mg/dL, further reduction of RC may significantly increase the probability of returning to normoglycemia from prediabetes.


Assuntos
Colesterol , Estado Pré-Diabético , Humanos , Estado Pré-Diabético/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Colesterol/sangue , Estudos Retrospectivos , Adulto , Glicemia/metabolismo , Glicemia/análise , China/epidemiologia , Modelos de Riscos Proporcionais , Idoso , Triglicerídeos/sangue , Povo Asiático , Fatores de Risco , Estudos de Coortes , População do Leste Asiático , Lipoproteínas
13.
J Infect Dis ; 230(Supplement_1): S82-S86, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39140718

RESUMO

Lyme disease is caused by the spirochete, Borrelia burgdorferi, which is transmitted by Ixodes spp ticks. The rise in Lyme disease cases since its discovery in the 1970s has reinforced the need for a vaccine. A vaccine based on B burgdorferi outer surface protein A (OspA) was approved by the Food and Drug Administration (FDA) several decades ago, but was pulled from the market a few years later, reportedly due to poor sales, despite multiple organizations concluding that it was safe and effective. Newer OspA-based vaccines are being developed and are likely to be available in the coming years. More recently, there has been a push to develop vaccines that target the tick vector instead of the pathogen to inhibit tick feeding and thus prevent transmission of tick-borne pathogens to humans and wildlife reservoirs. This review outlines the history of Lyme disease vaccines and this movement to anti-tick vaccine approaches.


Assuntos
Borrelia burgdorferi , Ixodes , Vacinas contra Doença de Lyme , Doença de Lyme , Doença de Lyme/prevenção & controle , Doença de Lyme/imunologia , Humanos , Animais , Borrelia burgdorferi/imunologia , Vacinas contra Doença de Lyme/imunologia , Ixodes/microbiologia , Vacinação , Proteínas da Membrana Bacteriana Externa/imunologia , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/administração & dosagem , Antígenos de Superfície/imunologia , Lipoproteínas/imunologia
14.
Bull Math Biol ; 86(9): 112, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39093509

RESUMO

Macrophages in atherosclerotic lesions exhibit a spectrum of behaviours or phenotypes. The phenotypic distribution of monocyte-derived macrophages (MDMs), its correlation with MDM lipid content, and relation to blood lipoprotein densities are not well understood. Of particular interest is the balance between low density lipoproteins (LDL) and high density lipoproteins (HDL), which carry bad and good cholesterol respectively. To address these issues, we have developed a mathematical model for early atherosclerosis in which the MDM population is structured by phenotype and lipid content. The model admits a simpler, closed subsystem whose analysis shows how lesion composition becomes more pathological as the blood density of LDL increases relative to the HDL capacity. We use asymptotic analysis to derive a power-law relationship between MDM phenotype and lipid content at steady-state. This relationship enables us to understand why, for example, lipid-laden MDMs have a more inflammatory phenotype than lipid-poor MDMs when blood LDL lipid density greatly exceeds HDL capacity. We show further that the MDM phenotype distribution always attains a local maximum, while the lipid content distribution may be unimodal, adopt a quasi-uniform profile or decrease monotonically. Pathological lesions exhibit a local maximum in both the phenotype and lipid content MDM distributions, with the maximum at an inflammatory phenotype and near the lipid content capacity respectively. These results illustrate how macrophage heterogeneity arises in early atherosclerosis and provide a framework for future model validation through comparison with single-cell RNA sequencing data.


Assuntos
Aterosclerose , Lipoproteínas HDL , Lipoproteínas LDL , Macrófagos , Conceitos Matemáticos , Fenótipo , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Aterosclerose/patologia , Aterosclerose/metabolismo , Aterosclerose/sangue , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/sangue , Lipoproteínas HDL/sangue , Lipoproteínas HDL/metabolismo , Modelos Cardiovasculares , Metabolismo dos Lipídeos , Lipoproteínas/metabolismo , Lipoproteínas/sangue , Simulação por Computador
15.
Sci Rep ; 14(1): 19120, 2024 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-39155305

RESUMO

Cardiovascular disease is one of the leading causes of death worldwide. Evidence suggests that alterations in the gut microbiome could play a role in cardiovascular diseases, including heart failure. The purpose of this study was to evaluate the effect of synbiotics on serum paraoxonase 1(PON1), soluble CD163/soluble TNF-like weak inducer of apoptosis (sCD163/sTWEAK), and lipid profile, which are involved in heart failure in patients with chronic heart failure. In this triple-blind randomized clinical trial, 90 eligible patients were included in the study. They were randomly assigned to receive one capsule (500 mg) of synbiotics or a placebo daily for ten weeks. Serum PON1, sCD163/sTWEAK, and lipid profiles were measured at the beginning and end of the study. The data were analyzed by SPSS 24, and the p-value < 0.05 was considered statistically significant. Among 90 patients who met the inclusion criteria, 80 completed the study. The primary outcomes showed a small effect on sTWEAK, with an adjusted standard mean difference (SMD) of 0.2. However, no significant changes were observed in sCD163/sTWEAK (SMD: 0.16). Secondary outcomes indicated no changes in PON1, total cholesterol (TC), or LDL-C levels. However, there was an increase in HDL-C levels (adjusted SMD: 0.46, 95% CI: 0.02-0.91) and a decrease in TG and TC/HDL levels (adjusted SMD: - 0.5 and - 0.3, respectively) in the synbiotic group. A favorable effect of synbiotics on sTWEAK, HDL, TG, and TC/HDL of patients with heart failure was observed, but no statistically significant effect was found on sCD163/sTWEAK, PON1, LDL, and TC factors.


Assuntos
Arildialquilfosfatase , Insuficiência Cardíaca , Simbióticos , Humanos , Arildialquilfosfatase/sangue , Masculino , Feminino , Simbióticos/administração & dosagem , Insuficiência Cardíaca/sangue , Pessoa de Meia-Idade , Idoso , Receptores de Superfície Celular/sangue , Antígenos CD/sangue , Citocina TWEAK/sangue , Lipoproteínas/sangue , Doença Crônica , Biomarcadores/sangue , Antígenos de Diferenciação Mielomonocítica
16.
Hum Genomics ; 18(1): 85, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39090729

RESUMO

Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of ß-sitosterol and campesterol using the Metabolon platform from Qatar Biobank (QBB) and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms associated with ß-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. Evaluation of a polygenic risk score devised from European GWAS data showed moderate performance when applied to QBB (adjusted-R2 = 0.082). These findings provide new insights into the genetic architecture of phytosterol metabolism while showing the importance including under-represented populations in future GWAS studies.


Assuntos
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Estudo de Associação Genômica Ampla , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Polimorfismo de Nucleotídeo Único , Sitosteroides , Humanos , Fitosteróis/sangue , Fitosteróis/genética , Fitosteróis/efeitos adversos , Polimorfismo de Nucleotídeo Único/genética , Sitosteroides/sangue , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/sangue , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Masculino , Feminino , Enteropatias/genética , Enteropatias/sangue , Adulto , Colesterol/sangue , Colesterol/análogos & derivados , Hipercolesterolemia/genética , Hipercolesterolemia/sangue , Pessoa de Meia-Idade , Lipoproteínas/sangue , Lipoproteínas/genética , Transportadores de Cassetes de Ligação de ATP/genética
17.
Lipids Health Dis ; 23(1): 256, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39164739

RESUMO

BACKGROUND: Recent studies have implicated remnant cholesterol (RC) in the etiology, progression, and prognosis of cancer. However, very few of them concentrated on the study of the precise relationship between serum RC levels and cancer risk, leaving this subject unexplored. Consequently, this study aims to investigate the association between serum RC levels and 4 site-specific cancers, employing a dual approach that combines observational and mendelian randomization (MR) analysis. METHODS: Based on data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2020, this study collected data from18,067 participants. To rule out confounders, this study utilized weighted multivariable logistic regression and assessed non-linear associations using restricted cubic spline (RCS) regression, followed by two-piecewise linear regression. Sensitivity analysis conducted in this study included subgroup analysis, multiple imputation, outlier removal, and propensity score matching. To strengthen causal inference, this study employed univariable and multivariable MR analysis. The robustness and reliability of the findings were estimated by the application of replication and meta-analysis. RESULTS: The results of multivariable logistic regression analysis demonstrated a significant association between serum RC levels and breast cancer, showing that individuals in the higher logRC category had a higher risk of breast cancer compared to those in the lower category (Q3 vs. Q1: OR = 1.71, 95% CI: 1.01-2.88, P = 0.044). Weighted RCS revealed an inverted L-shape association between RC and the risk of breast cancer (P-nonlinear = 0.0386, P-overall = 0.010). Primary MR analysis provided evidence for an increased risk of breast (IVW: OR = 1.08, 95% CI: 1.03-1.12, P = 0.000951) and colorectal cancer (IVW: OR = 1.12, 95% CI: 1.00-1.24, P = 0.0476) associated with RC. However, the results of replication and meta-analysis did not support a significant causal association of RC with the risk of breast cancer (OR = 1.04, 95% CI: 0.95-1.13), lung cancer (OR = 0.95, 95% CI: 0.88-1.03), colorectal cancer (OR = 1.05, 95% CI: 0.92-1.19), and prostate cancer (OR = 1.01, 95% CI: 0.95-1.08). CONCLUSION: Although a non-linear relationship was observed in the cross-sectional study between remnant cholesterol levels and breast cancer risk, MR analyses failed to provide any causal evidence.


Assuntos
Colesterol , Análise da Randomização Mendeliana , Humanos , Feminino , Colesterol/sangue , Estudos Transversais , Pessoa de Meia-Idade , Masculino , Fatores de Risco , Neoplasias/sangue , Neoplasias/genética , Neoplasias/epidemiologia , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/epidemiologia , Adulto , Inquéritos Nutricionais , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/epidemiologia , Idoso , Modelos Logísticos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/epidemiologia , Lipoproteínas , Triglicerídeos
18.
Clin Sci (Lond) ; 138(17): 1039-1054, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39136693

RESUMO

Maternal high-fat diet intake has profound effects on the long-term health of offspring, predisposing them to a higher susceptibility to obesity and metabolic dysfunction-associated steatotic liver disease. However, the detailed mechanisms underlying the role of a maternal high-fat diet in hepatic lipid accumulation in offspring, especially at the weaning age, remain largely unclear. In this study, female C57BL/6J mice were randomly assigned to either a high-fat diet or a control diet, and lipid metabolism parameters were assessed in male offspring at weaning. Gut microbiota analysis and targeted metabolomics of short-chain fatty acids (SCFAs) in these offspring were further performed. Both in vivo and in vitro studies were conducted to explore the role of butyrate in hepatic cholesterol excretion in the liver and HepG2 cells. Our results showed that maternal high-fat feeding led to obesity and dyslipidemia, and exacerbated hepatic lipid accumulation in the livers of offspring at weaning. We observed significant decreases in the abundance of the Firmicutes phylum and the Allobaculum genus, known as producers of SCFAs, particularly butyrate, in the offspring of dams fed a high-fat diet. Additionally, maternal high-fat diet feeding markedly decreased serum butyrate levels and down-regulated ATP-binding cassette transporters G5 (ABCG5) in the liver, accompanied by decreased phosphorylated AMP-activated protein kinase (AMPK) and histone deacetylase 5 (HADC5) expressions. Subsequent in vitro studies revealed that butyrate could induce ABCG5 activation and alleviate lipid accumulation via the AMPK-pHDAC5 pathway in HepG2 cells. Moreover, knockdown of HDAC5 up-regulated ABCG5 expression and promoted cholesterol excretion in HepG2 cells. In conclusion, our study provides novel insights into how maternal high-fat diet feeding inhibits hepatic cholesterol excretion and down-regulates ABCG5 through the butyrate-AMPK-pHDAC5 pathway in offspring at weaning.


Assuntos
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Butiratos , Colesterol , Dieta Hiperlipídica , Microbioma Gastrointestinal , Fígado , Camundongos Endogâmicos C57BL , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Butiratos/metabolismo , Humanos , Fígado/metabolismo , Células Hep G2 , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Masculino , Colesterol/metabolismo , Colesterol/sangue , Gravidez , Camundongos , Metabolismo dos Lipídeos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/metabolismo , Obesidade/microbiologia , Dislipidemias/metabolismo , Dislipidemias/microbiologia , Dislipidemias/etiologia , Lipoproteínas
19.
ACS Appl Mater Interfaces ; 16(34): 44386-44398, 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39149774

RESUMO

Extracellular vesicles (EVs) are present in blood at much lower concentrations (5-6 orders of magnitude) compared to lipoprotein particles (LP). Because LP and EV overlap in size and density, isolating high-purity EVs is a significant challenge. While the current two-step sequential EV isolation process using size-expression chromatography (SEC) followed by a density gradient (DG) achieves high purity, the time-consuming ultracentrifugation (UC) step in DG hinders workflow efficiency. This paper introduces an optimized magnetic bead reagent, LipoMin, functionalized with glycosaminoglycans (GAGs), as a rapid alternative for LP removal during the second-step process in about 10 minutes. We evaluated LipoMin's efficacy on two sample types: (a) EV fractions isolated by size exclusion chromatography (SEC + LipoMin) and (b) the pellet obtained from ultracentrifugation (UC + LipoMin). The workflow is remarkably simple, involving a 10 min incubation with LipoMin followed by magnetic separation of the LP-depleted EV-containing supernatant. Results from enzyme-linked immunosorbent assay (ELISA) revealed that LipoMin removes 98.2% ApoB from SEC EV fractions, comparable to the LP removal ability of DG in the SEC + DG two-step process. Importantly, the EV yield (CD81 ELISA) remained at 93.0% and Western blot analysis confirmed that key EV markers, flotillin and CD81, were not compromised. Recombinant EV (rEV), an EV reference standard, was spiked into SEC EV fractions and recovered 89% of CD81 protein. For UC + LipoMin, ApoA1 decreased by 76.5% while retaining 90.7% of CD81. Notably, both colorectal cancer (CRC) and Alzheimer's disease (AD) samples processed by SEC + LipoMin and UC + LipoMin displayed clear expression of relevant EV and clinical markers. With a 10 min workflow (resulting in a 96% time saving compared to the traditional method), the LipoMin reagent offers a rapid and efficient alternative to DG for LP depletion, paving the way for a streamlined SEC + LipoMin two-step EV isolation process.


Assuntos
Cromatografia em Gel , Vesículas Extracelulares , Glicosaminoglicanos , Lipoproteínas , Ultracentrifugação , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Ultracentrifugação/métodos , Humanos , Lipoproteínas/química , Lipoproteínas/isolamento & purificação , Glicosaminoglicanos/química , Glicosaminoglicanos/isolamento & purificação
20.
J Am Heart Assoc ; 13(15): e034770, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39082393

RESUMO

BACKGROUND: The capacity of high-density lipoprotein cholesterol (HDL) to acquire free cholesterol (FC) from triglyceride-rich lipoproteins during lipoprotein lipase-dependent lipolysis in a process of reverse remnant cholesterol transport, has been proposed as a key biological function of HDL particles that underlies the U-shaped relationship between HDLcholesterol and cardiovascular diseases. Although reverse remnant cholesterol transport has been evaluated in a fasting state, it has never been explored under nonfasting conditions. METHODS AND RESULTS: FC transfer was evaluated in healthy men (n=78) before and throughout the postprandial phase up to 8 hours after consumption of a test meal. Postprandially, the capacity of HDL to acquire FC increased progressively, reaching a maximal mean value of 98.5%±22.5% 6 hours after meal intake (P<0.05). Analysis of the study population according to tertiles of postprandial variation of FC transfer identified subjects exhibiting reduced capacity of HDL to acquire FC (tertile 1), those for whom the capacity of HDL to acquire FC remained unchanged (tertile 2), and subjects characterized by an enhanced FC transfer during the postprandial phase (tertile 3). Across the tertiles, we found an inverse relationship between the maximal postprandial change in FC transfer to HDL and the degree of postprandial triglyceride response. CONCLUSIONS: Healthy individuals exhibiting exacerbated postprandial triglyceride response and reduced HDL cholesterol levels feature reduced FC transfer to HDL during the postprandial state. These data suggest that to normalize postprandial triglyceride response, 2 conditions need to be fulfilled: notably elevated FC transfer to HDL in the postprandial phase and increased levels of acceptor HDL particles.


Assuntos
Hipertrigliceridemia , Período Pós-Prandial , Triglicerídeos , Humanos , Masculino , Período Pós-Prandial/fisiologia , Triglicerídeos/sangue , Hipertrigliceridemia/sangue , Adulto , Lipoproteínas/sangue , Voluntários Saudáveis , Pessoa de Meia-Idade , HDL-Colesterol/sangue , Colesterol/sangue , Adulto Jovem , Lipoproteínas HDL/sangue , Biomarcadores/sangue , Fatores de Tempo
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