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1.
Clín. investig. arterioscler. (Ed. impr.) ; 36(2): 71-77, mar.-abr. 2024. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-231495

RESUMO

Introducción Recientemente se ha demostrado una relación inversa entre la concentración en sangre de la lipoproteína(a) (Lp[a]) y los triglicéridos (TG). A mayor tamaño de lipoproteínas de muy baja densidad (VLDL), mayor presencia de VLDL ricas en apoliproteína E (apo E) y en sujetos con genotipo apo E2/E2, Lp(a) más baja. El mecanismo de esta asociación contrapuesta es desconocido. El objetivo de nuestro análisis fue evaluar la correspondencia Lp(a)-TG en los pacientes atendidos en las Unidades de Lípidos incluidos en el registro de la Sociedad Española de Arteriosclerosis (SEA) comparando las diferentes dislipidemias. Pacientes y métodos Se incluyeron 5.275 usuarios de ≥ 18 años registrados antes del 31 de marzo de 2023, con datos de concentración de Lp(a) e información completa del perfil lipídico sin tratamiento. Resultados La media de edad fue de 53,0 ± 14,0 años, con 48% de mujeres. Un total de 9,5% (n = 502) tenían diabetes mellitus (DM) y 1.184 sujetos (22,4%) presentaban obesidad. La mediana de TG fue de 130 mg/dL (rango intercuartílico [IQR] 88,0-210) y de Lp(a) 55,0 nmol/L (IQR 17,9 -156). La concentración de Lp(a) mostró una asociación negativa con la de TG cuando los valores de estos superaban los 300 mg/dL. Los pacientes con TG > 1.000 mg/dL mostraron el menor nivel de Lp(a) 17,9 nmol/L y los usuarios con TG < 300 mg/dL, presentaron una media de Lp(a) de 60,1 nmol/L. En pacientes sin DM ni obesidad, la relación inversa de Lp(a)-TG fue especialmente importante (p < 0,001). La mediana de Lp(a) fue de 58,3 nmol/L en aquellos con TG < 300 mg/dL y 22,0 nmol/L si TG > 1.000 mg/dL. No se encontró asociación entre TG y Lp(a) en sujetos con DM y obesidad, ni en los que contaban con hipercolesterolemia familiar (HF). En los que padecen hiperlipemia combinada multifactorial con TG < 300 mg/dL la Lp(a) fue 64,6 nmol/L, en el rango de 300-399 mg/dL de TG la Lp(a) desciende hasta 38,8 nmol/L y hasta 22,3 nmol/L si TG > 1.000 mg/dL. Conclusiones ... (AU)


Background Recently, an inverse relationship between the blood concentration of lipoprotein(a) (Lp(a)) and triglycerides (TG) has been demonstrated. The larger the VLDL particle size, the greater the presence of VLDL rich in apoliprotein E and in subjects with the apoE2/E2 genotype, the lower Lp(a) concentration. The mechanism of this inverse association is unknown. The objective of this analysis was to evaluate the Lp(a)–TG association in patients treated at the lipid units included in the registry of the Spanish Society of Atherosclerosis (SEA) by comparing the different dyslipidemias. Patients and methods Five thousand two hundred and seventy-five subjects ≥18 years of age registered in the registry before March 31, 2023, with Lp(a) concentration data and complete lipid profile information without treatment were included. Results The mean age was 53.0 ± 14.0 years, with 48% women. The 9.5% of subjects (n = 502) had diabetes and the 22.4% (n = 1184) were obese. The median TG level was 130 mg/dL (IQR 88.0–210) and Lp(a) 55.0 nmol/L (IQR 17.9–156). Lp(a) concentration showed a negative association with TG concentration when TG values exceeded 300 mg/dL. Subjects with TG > 1000 mg/dL showed the lowest level of Lp(a), 17.9 nmol/L, and subjects with TG < 300 mg/dL had a mean Lp(a) concentration of 60.1 nmol/L. In subjects without diabetes or obesity, the inverse association of Lp(a)–TG was especially important (p < 0.001). The median Lp(a) was 58.3 nmol/L in those with TG < 300 mg/dL and 22.0 nmol/L if TG > 1000 mg/dL. No association was found between TG and Lp(a) in subjects with diabetes and obesity, nor in subjects with familial hypercholesterolemia. In subjects with multifactorial combined hyperlipemia with TG < 300 mg/dL, Lp(a) was 64.6 nmol/L; in the range of 300–399 mg/dL of TG, Lp(a) decreased to 38. 8 nmol/L, and up to 22.3 nmol/L when TG > 1000 mg/dL. Conclusions ... (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Lipoproteínas HDL , Triglicerídeos , Dislipidemias , Lipídeos , Espanha
2.
PeerJ ; 12: e17009, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38436035

RESUMO

Background: Inflammation and metabolic disorders are important factors in the occurrence and development of obesity complications. In this study, we investigated the protective effect and underlying mechanism of a novel pyrimidine-2,4-diamine derivative, Cyy-287, on mice fed a high-fat diet (HFD). Methods: The mice were randomly separated into four groups (n ≥ 7): control (regular diet), HFD, HFD with Cyy-287 (5 mg/kg), and HFD with Cyy-287 (20 mg/kg) following HFD feeding for 10 weeks. After a 10-week administration, ALT and AST enzymes, echocardiography, immunohistochemical (IHC), Western blot (WB), Masson and Sirius Red staining were used to evaluate functional and morphological changes to the heart and liver. Microsomes from the mouse liver were extracted to quantify the total amount of CYP450 enzymes after drug treatment. Results: Cyy-287 decreased the levels of serum glucose, LDL, TC, ALT, and AST activities in HFD-treated mice. However, Cyy-287 administration increased ejection fraction (EF) and fractional shortening (FS) index of the heart. Cyy-287 inhibited histopathological changes in the heart and liver; decreased inflammatory activity; significantly diminished p38 mitogen-activated protein kinase (MAPK), the nuclear factor-kappa B (NF-κB) axis, and sterol regulatory element-binding protein-1c (SREBP-1c); and upregulated the AMP-activated protein kinase (AMPK) pathway in HFD-treated mice. Cyy-287 restored the content of hepatic CYP450 enzymes. Conclusion: These findings demonstrated that Cyy-287 protected heart and liver cells from obesity-induced damage by inhibiting inflammation, fibrosis, and lipid synthesis.


Assuntos
Obesidade , Pirimidinas , Animais , Camundongos , Obesidade/complicações , Pirimidinas/farmacologia , Diaminas , Inflamação/tratamento farmacológico , Fibrose , Lipídeos
3.
J Transl Med ; 22(1): 225, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429794

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent worldwide, emerging as a significant health issue on a global scale. Berberine exhibits potential for treating NAFLD, but clinical evidence remains inconclusive. This meta-analysis was conducted to assess the efficacy and safety of berberine for treating NAFLD. METHODS: This study was registered with PROSPERO (No. CRD42023462338). Identification of randomized controlled trials (RCTs) involved searching 6 databases covering the period from their initiation to 9 September 2023. The primary outcomes comprised liver function markers such as glutamyl transpeptidase (GGT), alanine transaminase (ALT), aspartate transaminase (AST), lipid indices including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), homeostasis model assessment for insulin resistance (HOMA-IR) and body mass index (BMI). Review Manager 5.4 and STATA 17.0 were applied for analysis. RESULTS: Among 10 RCTs involving 811 patients, berberine demonstrated significant reductions in various parameters: ALT (standardized mean difference (SMD) = - 0.72), 95% confidence interval (Cl) [- 1.01, - 0.44], P < 0.00001), AST (SMD = - 0.79, 95% CI [- 1.17, - 0.40], P < 0.0001), GGT (SMD = - 0.62, 95% CI [- 0.95, - 0.29], P = 0.0002), TG (SMD = - 0.59, 95% CI [- 0.86, - 0.31], P < 0.0001), TC(SMD = - 0.74, 95% CI [- 1.00, - 0.49], P < 0.00001), LDL-C (SMD = - 0.53, 95% CI [- 0.88, - 0.18], P = 0.003), HDL-C (SMD = - 0.51, 95% CI [- 0.12, 1.15], P = 0.11), HOMA-IR (SMD = - 1.56, 95% CI [- 2.54, - 0.58], P = 0.002), and BMI (SMD = - 0.58, 95% CI [- 0.77, - 0.38], P < 0.00001). Importantly, Berberine exhibited a favorable safety profile, with only mild gastrointestinal adverse events reported. CONCLUSION: This meta-analysis demonstrates berberine's efficacy in improving liver enzymes, lipid profile, and insulin sensitivity in NAFLD patients. These results indicate that berberine shows promise as an adjunct therapy for NAFLD. Trial registration The protocol was registered with PROSPERO (No. CRD42023462338). Registered on September 27, 2023.


Assuntos
Berberina , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Humanos , Berberina/efeitos adversos , HDL-Colesterol , LDL-Colesterol , Lipídeos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Resultado do Tratamento , Triglicerídeos
4.
Clin Chem ; 70(3): 528-537, 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38431279

RESUMO

BACKGROUND: Lipid profiling is central for coronary artery disease (CAD) risk assessment. Nonadherence or unreported use of lipid-lowering drugs, particularly statins, can significantly complicate the association between lipid profile measures and CAD clinical outcomes. By combining medication history evaluation with statin analysis in plasma, we determined the effects of inaccurately reported statin use on lipid profile measures and their association with CAD risk. METHODS: We compared medication history of statin use with statin concentration measurements, by liquid chromatography-tandem mass spectrometry, in 690 participants undergoing coronary angiography (63 ± 11 years of age). Nominal logistic regression was employed to model CAD diagnosis with statin measurements, phenotypic, and lipid profile characteristics. RESULTS: Medication history of statin use was confirmed by statin assay for 81% of the patients. Surprisingly, statins were detected in 46% of patients without statin use records. Nonreported statin use was disproportionately higher among older participants. Stratifying samples by statin history resulted in underestimated LDL-lipid measures. Apolipoprotein B concentrations had a significant inverse CAD association, which became nonsignificant upon re-stratification using the statin assay data. CONCLUSIONS: Our study uncovered prominent discrepancies between medication records and actual statin use measured by mass spectrometry. We showed that inaccurate statin use assessments may lead to overestimation and underestimation of LDL levels in statin user and nonuser categories, exaggerating the reverse epidemiology association between LDL levels and CAD diagnosis. Combining medication history and quantitative statin assay data can significantly improve the design, analysis, and interpretation of clinical and epidemiological studies.


Assuntos
Doença da Artéria Coronariana , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos , Medição de Risco , Fatores de Risco , Pessoa de Meia-Idade , Idoso
5.
Anal Chem ; 96(10): 4266-4274, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38469638

RESUMO

We introduce a novel approach for comprehensive molecular profiling in biological samples. Our single-section methodology combines quantitative mass spectrometry imaging (Q-MSI) and a single step extraction protocol enabling lipidomic and proteomic liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis on the same tissue area. The integration of spatially correlated lipidomic and proteomic data on a single tissue section allows for a comprehensive interpretation of the molecular landscape. Comparing Q-MSI and Q-LC-MS/MS quantification results sheds new light on the effect of MSI and related sample preparation. Performing MSI before Q-LC-MS on the same tissue section led to fewer protein identifications and a lower correlation between lipid quantification results. Also, the critical role and influence of internal standards in Q-MSI for accurate quantification is highlighted. Testing various slide types and the evaluation of different workflows for single-section spatial multiomics analysis emphasized the need for critical evaluation of Q-MSI data. These findings highlight the necessity for robust quantification methods comparable to current gold-standard LC-MS/MS techniques. The spatial information from MSI allowed region-specific insights within heterogeneous tissues, as demonstrated for glioblastoma multiforme. Additionally, our workflow demonstrated the efficiency of a single step extraction for lipidomic and proteomic analyses on the same tissue area, enabling the examination of significantly altered proteins and lipids within distinct regions of a single section. The integration of these insights into a lipid-protein interaction network expands the biological information attainable from a tissue section, highlighting the potential of this comprehensive approach for advancing spatial multiomics research.


Assuntos
Lipidômica , Espectrometria de Massas em Tandem , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Cromatografia Líquida , Fluxo de Trabalho , Proteômica/métodos , Lipídeos/análise
6.
Sci Rep ; 14(1): 6089, 2024 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-38480746

RESUMO

Coronary artery disease (CAD) often leads to adverse events resulting in significant disease burdens. Underlying risk factors often remain inapparent prior to disease incidence and the cardiovascular (CV) risk is not exclusively explained by traditional risk factors. Platelets inherently promote atheroprogression and enhanced platelet functions and distinct platelet lipid species are associated with disease severity in patients with CAD. Lipidomics data were acquired using mass spectrometry and processed alongside clinical data applying machine learning to model estimates of an increased CV risk in a consecutive CAD cohort (n = 595). By training machine learning models on CV risk measurements, stratification of CAD patients resulted in a phenotyping of risk groups. We found that distinct platelet lipids are associated with an increased CV or bleeding risk and independently predict adverse events. Notably, the addition of platelet lipids to conventional risk factors resulted in an increased diagnostic accuracy of patients with adverse CV events. Thus, patients with aberrant platelet lipid signatures and platelet functions are at elevated risk to develop adverse CV events. Machine learning combining platelet lipidome data and common clinical parameters demonstrated an increased diagnostic value in patients with CAD and might improve early risk discrimination and classification for CV events.


Assuntos
Carnitina/análogos & derivados , Doença da Artéria Coronariana , Humanos , Doença da Artéria Coronariana/diagnóstico , Hemorragia , Fatores de Risco , Aprendizado de Máquina , Lisofosfolipídeos , Lipídeos
7.
Cells ; 13(5)2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38474328

RESUMO

Adaptation to changes in the environment depends, in part, on signaling between plant organs to integrate adaptive response at the level of the whole organism. Changes in the delivery of hormones from one organ to another through the vascular system strongly suggest that hormone transport is involved in the transmission of signals over long distances. However, there is evidence that, alternatively, systemic responses may be brought about by other kinds of signals (e.g., hydraulic or electrical) capable of inducing changes in hormone metabolism in distant organs. Long-distance transport of hormones is therefore a matter of debate. This review summarizes arguments for and against the involvement of the long-distance transport of cytokinins in signaling mineral nutrient availability from roots to the shoot. It also assesses the evidence for the role of abscisic acid (ABA) and jasmonates in long-distance signaling of water deficiency and the possibility that Lipid-Binding and Transfer Proteins (LBTPs) facilitate the long-distance transport of hormones. It is assumed that proteins of this type raise the solubility of hydrophobic substances such as ABA and jasmonates in hydrophilic spaces, thereby enabling their movement in solution throughout the plant. This review collates evidence that LBTPs bind to cytokinins, ABA, and jasmonates and that cytokinins, ABA, and LBTPs are present in xylem and phloem sap and co-localize at sites of loading into vascular tissues and at sites of unloading from the phloem. The available evidence indicates a functional interaction between LBTPs and these hormones.


Assuntos
Ácido Abscísico , Reguladores de Crescimento de Plantas , Reguladores de Crescimento de Plantas/metabolismo , Ácido Abscísico/metabolismo , Citocininas/metabolismo , Plantas/metabolismo , Hormônios , Lipídeos
8.
Molecules ; 29(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38474451

RESUMO

This study focuses on the behavior of volatile organic compounds in beef after irradiation with 1 MeV accelerated electrons with doses ranging from 0.25 kGy to 5 kGy to find reliable dose-dependent markers that could be used for establishing an effective dose range for beef irradiation. GC/MS analysis revealed that immediately after irradiation, the chemical yield and accumulation rate of lipid oxidation-derived aldehydes was higher than that of protein oxidation-derived aldehydes. The nonlinear dose-dependent relationship of the concentration of volatile organic compounds was explained using a mathematical model based on the simultaneous occurrence of two competing processes: decomposition of volatile compounds due to direct and indirect action of accelerated electrons, and accumulation of volatile compounds due to decomposition of other compounds and biomacromolecules. A four-day monitoring of the beef samples stored at 4 °C showed that lipid oxidation-derived aldehydes, protein oxidation-derived aldehydes and alkanes as well as alcohol ethanol as an indicator of bacterial activity were dose-dependent markers of biochemical processes occurring in the irradiated beef samples during storage: oxidative processes during direct and indirect action of irradiation, oxidation due to the action of reactive oxygen species, which are always present in the product during storage, and microbial-enzymatic processes. According to the mathematical model of the change in the concentrations of lipid oxidation-derived aldehydes over time in the beef samples irradiated with different doses, it was found that doses ranging from 0.25 kGy to 1 kGy proved to be most effective for beef irradiation with accelerated electrons, since this dose range decreases the bacterial content without considerable irreversible changes in chemical composition of chilled beef during storage.


Assuntos
Compostos Orgânicos Voláteis , Animais , Bovinos , Elétrons , Oxirredução , Lipídeos , Aldeídos/análise
9.
Molecules ; 29(5)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38474536

RESUMO

The lipid phosphatase Ship2 interacts with the EphA2 receptor by forming a heterotypic Sam (sterile alpha motif)-Sam complex. Ship2 works as a negative regulator of receptor endocytosis and consequent degradation, and anti-oncogenic effects in cancer cells should be induced by hindering its association with EphA2. Herein, a computational approach is presented to investigate the relationship between Ship2-Sam/EphA2-Sam interaction and cancer onset and further progression. A search was first conducted through the COSMIC (Catalogue of Somatic Mutations in Cancer) database to identify cancer-related missense mutations positioned inside or close to the EphA2-Sam and Ship2-Sam reciprocal binding interfaces. Next, potential differences in the chemical-physical properties of mutant and wild-type Sam domains were evaluated by bioinformatics tools based on analyses of primary sequences. Three-dimensional (3D) structural models of mutated EphA2-Sam and Ship2-Sam domains were built as well and deeply analysed with diverse computational instruments, including molecular dynamics, to classify potentially stabilizing and destabilizing mutations. In the end, the influence of mutations on the EphA2-Sam/Ship2-Sam interaction was studied through docking techniques. This in silico approach contributes to understanding, at the molecular level, the mutation/cancer relationship by predicting if amino acid substitutions could modulate EphA2 receptor endocytosis.


Assuntos
Neoplasias , Receptor EphA2 , Motivo Estéril alfa , Receptor EphA2/química , Ligação Proteica , Mutação , Monoéster Fosfórico Hidrolases/metabolismo , Lipídeos
10.
BMC Public Health ; 24(1): 682, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438994

RESUMO

BACKGROUND: Type 2 diabetes mellitus represents a multifaceted disorder characterized by intricate pathophysiological mechanisms, encompassing diminished insulin secretion, augmented hepatic glucose production, and heightened insulin resistance. This study aims to assess the sex (Male and Female only) and family history-based differences in the prevalence of T2DM and explore the determinants contributing to this disparity among clinical patients. SUBJECTS AND METHODS: The study encompassed a diverse pool of clinical patients, encompassing both individuals with diabetes and those without the condition, who had previously sought medical attention for clinical checkups at healthcare centers. The collected data included essential parameters such as blood pressure, weight, height, smoking habits, educational background, and physical activity levels. To ensure methodological rigor and data accuracy, blood pressure measurements adhered to the stringent guidelines set forth by the World Health Organization. RESULTS: Participants of the present study reported diabetes, among which notable findings emerged regarding health indicators. It was observed that the prevalence of high blood pressure, obesity, and high blood cholesterol exhibited a statistically significant increase among the female participants, underscoring the sex-based disparities in these health parameters. The male population aged 60 or older, the presence of a family history of DM accentuated this risk, resulting in a striking 3.1 times higher prevalence compared to females, who exhibited a 2.4 times higher risk (OR = 2.4, p = 0.0008). This intriguing relationship between diabetes and cholesterol levels was not limited to sex. Both male (OR = 2.47) and female (OR = 2.1) diabetes patients displayed highly significant associations with cholesterol levels. The risk of T2DM was significantly associated with triglycerides in both sexes (1.58 times higher in males, and 1.71 times higher in females). CONCLUSIONS: The significance of hypertension as a comorbidity in T2DM, highlighting sex-specific associations and the potential impact of a family history of diabetes on blood pressure. Our findings emphasize the importance of considering lipid profiles, obesity, and their sex-specific associations when assessing and managing diabetes risk. Comprehensive diabetes care should include strategies for lipid control, weight management, and cardiovascular risk reduction, tailored to the individual's sex and specific risk profile.


Assuntos
Diabetes Mellitus Tipo 2 , Hipertensão , Humanos , Feminino , Masculino , Diabetes Mellitus Tipo 2/epidemiologia , Prevalência , Hipertensão/epidemiologia , Obesidade , Colesterol , Lipídeos
11.
Int J Nanomedicine ; 19: 1683-1697, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38445226

RESUMO

Introduction: Cartilage regeneration is a challenging issue due to poor regenerative properties of tissues. Electrospun nanofibers hold enormous potentials for treatments of cartilage defects. However, nanofibrous materials used for the treatment of cartilage defects often require physical and/or chemical modifications to promote the adhesion, proliferation, and differentiation of cells. Thus, it is highly desirable to improve their surface properties with functionality. We aim to design hydrophilic, adhesive, and compound K-loaded nanofibers for treatments of cartilage defects. Methods: Hydrophilic and adhesive compound K-containing polycaprolactone nanofibers (CK/PCL NFs) were prepared by coatings of gallic acid-conjugated chitosan (CHI-GA). Therapeutic effects of CHI-GA/CK/PCL NFs were assessed by the expression level of genes involved in the cartilage matrix degradation, inflammatory response, and lipid accumulations in the chondrocytes. In addition, Cartilage damage was evaluated by safranin O staining and immunohistochemistry of interleukin-1ß (IL-1ß) using OA animal models. To explore the pathway associated with therapeutic effects of CHI-GA/CK/PCL NFs, cell adhesion, phalloidin staining, and the expression level of integrins and peroxisome proliferator-activated receptor (PPARs) were evaluated. Results: CHI-GA-coated side of the PCL NFs showed hydrophilic and adhesive properties, whereas the unmodified opposite side remained hydrophobic. The expression levels of genes involved in the degradation of the cartilage matrix, inflammation, and lipogenesis were decreased in CHI-GA/CK/PCL NFs owing to the release of CK. In vivo implantation of CHI-GA/CK/PCL NFs into the cartilage reduced cartilage degradation induced by destabilization of the medial meniscus (DMM) surgery. Furthermore, the accumulation of lipid deposition and expression levels of IL-1ß was reduced through the upregulation of PPAR. Conclusion: CHI-GA/CK/PCL NFs were effective in the treatments of cartilage defects by inhibiting the expression levels of genes involved in cartilage degradation, inflammation, and lipogenesis as well as reducing lipid accumulation and the expression level of IL-1ß via increasing PPAR.


Assuntos
Quitosana , Ginsenosídeos , Nanofibras , Animais , Receptores Ativados por Proliferador de Peroxissomo , Cartilagem , Inflamação/tratamento farmacológico , Regeneração , Lipídeos
12.
Rev Med Suisse ; 20(864): 472-479, 2024 Mar 06.
Artigo em Francês | MEDLINE | ID: mdl-38445676

RESUMO

Dyslipidemia is a modifiable risk factor for cardiovascular diseases. Recommendations are based on achieving LDL-C target levels, but it is essential to assess the benefits of intensifying lipid-lowering therapy in terms of absolute risk reduction of cardiovascular events across different risk groups. Current data on the absolute benefits of the latest lipid-lowering treatments are more limited in comparison with statins. A recent analysis showed that adding a second lipid-lowering treatment only reduces the absolute cardiovascular risk in patients at very high and high cardiovascular risk, without a substantial benefit in patients at moderate or low cardiovascular risk, as mentioned in the recent recommendations free of conflict of interest and published in the British Medical Journal.


La dyslipidémie est un facteur de risque modifiable des maladies cardiovasculaires. Les recommandations sont basées sur l'atteinte de valeurs cibles du LDL-C mais il est essentiel d'évaluer les avantages de l'intensification du traitement hypolipémiant en termes de réduction du risque absolu d'événements cardiovasculaires dans les différents groupes à risque. Les données actuelles sur le bénéfice des nouveaux traitements hypolipémiants sont plus limitées comparées aux statines. Une analyse récente a montré que l'addition d'un second traitement hypolipémiant réduit le risque cardiovasculaire (CV) absolu uniquement chez les patients avec un risque CV très élevé ou élevé, sans bénéfice absolu substantiel chez les patients à risque CV modéré ou faible, ce qui a été repris des recommandations internationales sans conflit d'intérêts dans le British Medical Journal.


Assuntos
Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Pacientes , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fatores de Risco , Lipídeos
13.
J Mass Spectrom ; 59(3): e5008, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38445816

RESUMO

Given the complexity of nervous tissues, understanding neurochemical pathophysiology puts high demands on bioanalytical techniques with respect to specificity and sensitivity. Mass spectrometry imaging (MSI) has evolved to become an important, biochemical imaging technology for spatial biology in biological and translational research. The technique facilitates comprehensive, sensitive elucidation of the spatial distribution patterns of drugs, lipids, peptides, and small proteins in situ. Matrix-assisted laser desorption ionization (MALDI)-based MSI is the dominating modality due to its broad applicability and fair compromise of selectivity, sensitivity price, throughput, and ease of use. This is particularly relevant for the analysis of spatial lipid patterns, where no other comparable spatial profiling tools are available. Understanding spatial lipid biology in nervous tissue is therefore a key and emerging application area of MSI research. The aim of this review is to give a concise guide through the MSI workflow for lipid imaging in central nervous system (CNS) tissues and essential parameters to consider while developing and optimizing MSI assays. Further, this review provides a broad overview of key developments and applications of MALDI MSI-based spatial neurolipidomics to map lipid dynamics in neuronal structures, ultimately contributing to a better understanding of neurodegenerative disease pathology.


Assuntos
Doenças Neurodegenerativas , Humanos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Doenças Neurodegenerativas/diagnóstico por imagem , Fluxo de Trabalho , Encéfalo/diagnóstico por imagem , Lipídeos
14.
BMJ Open ; 14(3): e078983, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38448070

RESUMO

INTRODUCTION: Chronic autoimmune (type 1 diabetes and coeliac disease) and metabolic/cardiovascular (type 2 diabetes, dyslipidaemia, hypertension) diseases are highly prevalent across all age ranges representing a major public health burden. Universal screening for prediction/early identification of these conditions is a potential tool for reducing their impact on the general population. The aim of this study is to assess whether universal screening using capillary blood sampling is feasible at a population-based level. METHODS AND ANALYSIS: This is a low-risk interventional, single-centre, pilot study for a population-based screening programme denominated UNISCREEN. Participants are volunteers aged 1-100 who reside in the town of Cantalupo (Milan, Italy) undergoing: (1) interview collecting demographics, anthropometrics and medical history; (2) capillary blood collection for measurement of type 1 diabetes and coeliac disease-specific autoantibodies and immediate measurement of glucose, glycated haemoglobin and lipid panel by point-of-care devices; (3) venous blood sampling to confirm autoantibody-positivity; (4) blood pressure measurement; (5) fulfilment of a feasibility and acceptability questionnaire. The outcomes are the assessment of feasibility and acceptability of capillary blood screening, the prevalence of presymptomatic type 1 diabetes and undiagnosed coeliac disease, distribution of glucose categories, lipid panel and estimate of cardiovascular risk in the study population. With approximately 3000 inhabitants, the screened population is expected to encompass at least half of its size, approaching nearly 1500 individuals. ETHICS AND DISSEMINATION: This protocol and the informed consent forms have been reviewed and approved by the San Raffaele Hospital Ethics Committee (approval number: 131/INT/2022). Written informed consent is obtained from all study participants or their parents if aged <18. Results will be published in scientific journals and presented at meetings. CONCLUSIONS: If proven feasible and acceptable, this universal screening model would pave the way for larger-scale programmes, providing an opportunity for the implementation of innovative public health programmes in the general population. TRIAL REGISTRATION NUMBER: NCT05841719.


Assuntos
Doenças Cardiovasculares , Doença Celíaca , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Humanos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Projetos Piloto , Doença Celíaca/diagnóstico , Doença Celíaca/epidemiologia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Autoanticorpos , Glucose , Lipídeos
15.
Front Immunol ; 15: 1335333, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38449872

RESUMO

Background and objective: Macrophages play a crucial and dichotomous role cardiac repair following myocardial ischemia-reperfusion, as they can both facilitate tissue healing and contribute to injury. This duality is intricately linked to environmental factors, and the identification of macrophage subtypes within the context of myocardial ischemia-reperfusion injury (MIRI) may offer insights for the development of more precise intervention strategies. Methods: Specific marker genes were used to identify macrophage subtypes in GSE227088 (mouse single-cell RNA sequencing dataset). Genome Set Enrichment Analysis (GSEA) was further employed to validate the identified LAM subtypes. Trajectory analysis and single-cell regulatory network inference were executed using the R packages Monocle2 and SCENIC, respectively. The conservation of LAM was verified using human ischemic cardiomyopathy heart failure samples from the GSE145154 (human single-cell RNA sequencing dataset). Fluorescent homologous double-labeling experiments were performed to determine the spatial localization of LAM-tagged gene expression in the MIRI mouse model. Results: In this study, single-cell RNA sequencing (scRNA-seq) was employed to investigate the cellular landscape in ischemia-reperfusion injury (IRI). Macrophage subtypes, including a novel Lipid-Associated Macrophage (LAM) subtype characterized by high expression of Spp1, Trem2, and other genes, were identified. Enrichment and Progeny pathway analyses highlighted the distinctive functional role of the SPP1+ LAM subtype, particularly in lipid metabolism and the regulation of the MAPK pathway. Pseudotime analysis revealed the dynamic differentiation of macrophage subtypes during IRI, with the activation of pro-inflammatory pathways in specific clusters. Transcription factor analysis using SCENIC identified key regulators associated with macrophage differentiation. Furthermore, validation in human samples confirmed the presence of SPP1+ LAM. Co-staining experiments provided definitive evidence of LAM marker expression in the infarct zone. These findings shed light on the role of LAM in IRI and its potential as a therapeutic target. Conclusion: In conclusion, the study identifies SPP1+ LAM macrophages in ischemia-reperfusion injury and highlights their potential in cardiac remodeling.


Assuntos
Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Humanos , Animais , Camundongos , Traumatismo por Reperfusão Miocárdica/genética , Genes Reporter , Macrófagos , Lipídeos , Glicoproteínas de Membrana , Receptores Imunológicos
16.
Proc Natl Acad Sci U S A ; 121(11): e2307813120, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38437570

RESUMO

Lipid nanoparticles (LNPs) largely rely on ionizable lipids to yield successful nucleic acid delivery via electrostatic disruption of the endosomal membrane. Here, we report the identification and evaluation of ionizable lipids containing a thiophene moiety (Thio-lipids). The Thio-lipids can be readily synthesized via the Gewald reaction, allowing for modular lipid design with functional constituents at various positions of the thiophene ring. Through the rational design of ionizable lipid structure, we prepared 47 Thio-lipids and identified some structural criteria required in Thio-lipids for efficient mRNA (messenger RNA) encapsulation and delivery in vitro and in vivo. Notably, none of the tested lipids have a pH-response profile like traditional ionizable lipids, potentially due to the electron delocalization in the thiophene core. Placement of the tails and localization of the ionizable headgroup in the thiophene core can endow the nanoparticles with the capability to reach various tissues. Using high-throughput formulation and barcoding techniques, we optimized the formulations to select two top lipids-20b and 29d-and investigated their biodistribution in mice. Lipid 20b enabled LNPs to transfect the liver and spleen, and 29d LNP transfected the lung and spleen. Unexpectedly, LNP with lipid 20b was especially potent in mRNA delivery to the retina with no acute toxicity, leading to the successful delivery to the photoreceptors and retinal pigment epithelium in non-human primates.


Assuntos
Pulmão , Retina , Animais , Camundongos , Distribuição Tecidual , RNA Mensageiro/genética , Lipídeos
17.
Pestic Biochem Physiol ; 199: 105757, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38458660

RESUMO

Fenhexamid are fungicides that act against plant pathogens by inhibiting sterol biosynthesis. Nonetheless, it can trigger endocrine disruption and promote breast cancer cell growth. In a recent study, we investigated the mechanism underlying the lipid accumulation induced by fenhexamid hydroxyanilide fungicides in 3 T3-L1 adipocytes. To examine the estrogen receptor alpha (ERα)-agonistic effect, ER transactivation assay using the ERα-HeLa-9903 cell line was applied, and fenhexamid-induced ERα agonist effect was confirmed. Further confirmation that ERα-dependent lipid accumulation occurred was provided by treating 3 T3-L1 adipocytes with Methyl-piperidino-pyrazole hydrate (MPP), an ERα-selective antagonist. Fenhexamid mimicked the actions of ERα agonists and impacted lipid metabolism, and its mechanism involves upregulation of the expression of transcription factors that facilitate adipogenesis and lipogenesis. Additionally, it stimulated the expression of peroxisome proliferator-activated receptor (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), fatty acid synthase (FAS), and sterol regulatory element-binding protein 1 (SREBP1) and significantly elevated the expression of fatty acid-binding protein 4 (FABP4). In contrast, in combination with an ERα-selective antagonist, fenhexamid suppressed the expression of adipogenic/lipogenic transcription factors. These results suggest that fenhexamid affects the endocrine system and leads to lipid accumulation by interfering with processes influenced by ERα activation.


Assuntos
Amidas , Receptor alfa de Estrogênio , Fungicidas Industriais , Camundongos , Animais , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Fungicidas Industriais/toxicidade , Fungicidas Industriais/metabolismo , Adipócitos/metabolismo , Adipogenia , Metabolismo dos Lipídeos , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/farmacologia , Lipídeos , Células 3T3-L1 , PPAR gama/metabolismo
18.
Pestic Biochem Physiol ; 199: 105756, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38458693

RESUMO

Cryptocaryons irritans is a ciliate parasite responsible for cryptocaryoniasis, leading to considerable economic losses in aquaculture. It is typically managed using a copper-zinc alloy (CZA), effectively diminishing C. irritans infection rates while ensuring the safety of aquatic organisms. Nevertheless, the precise mechanism underlying cuproptosis induced C. irritans mortality following exposure to CZA remains enigmatic. Therefore, this study delves into assessing the efficacy of CZA, investigate cuproptosis as a potential mechanism of CZA action against C. irritans, and determine the alterations in antioxidant enzymes, peroxidation, and lipid metabolism. The mRNA expression of dihydrolipoamide S-acetyltransferase was upregulated after 40 and 70 min, while aconitase 1 was implicated in cuproptosis following 70 min of CZA exposure. Furthermore, the relative mRNA levels of glutathione reductase experienced a significant increase after 40 and 70 min of CZA exposure. In contrast, the relative mRNA levels of glutathione S-transferase and phospholipid-hydroperoxide glutathione peroxidase were significantly decreased after 70 min, suggesting a disruption in antioxidant defense and an imbalance in copper ions. Lipidomics results also unveiled an elevation in glycerophospholipids metabolism and the involvement of the lipoic acid pathway, predominantly contributing to cuproptosis. In summary, exposure to CZA induces cuproptosis in C. irritans, impacts glutathione-related enzymes, and alters glycerophospholipids, consequently triggering lipid oxidation.


Assuntos
Infecções por Cilióforos , Doenças dos Peixes , Perciformes , Animais , Infecções por Cilióforos/parasitologia , Cobre/toxicidade , Ligas , Antioxidantes , Perciformes/parasitologia , Doenças dos Peixes/parasitologia , Metabolismo dos Lipídeos , RNA Mensageiro , Glicerofosfolipídeos , Lipídeos , Zinco/toxicidade
19.
Metabolomics ; 20(2): 37, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459207

RESUMO

BACKGROUND: Lipids play key roles in numerous biological processes, including energy storage, cell membrane structure, signaling, immune responses, and homeostasis, making lipidomics a vital branch of metabolomics that analyzes and characterizes a wide range of lipid classes. Addressing the complex etiology, age-related risk, progression, inflammation, and research overlap in conditions like Alzheimer's Disease, Parkinson's Disease, Cardiovascular Diseases, and Cancer poses significant challenges in the quest for effective therapeutic targets, improved diagnostic markers, and advanced treatments. Mass spectrometry is an indispensable tool in clinical lipidomics, delivering quantitative and structural lipid data, and its integration with technologies like Liquid Chromatography (LC), Magnetic Resonance Imaging (MRI), and few emerging Matrix-Assisted Laser Desorption Ionization- Imaging Mass Spectrometry (MALDI-IMS) along with its incorporation into Tissue Microarray (TMA) represents current advances. These innovations enhance lipidomics assessment, bolster accuracy, and offer insights into lipid subcellular localization, dynamics, and functional roles in disease contexts. AIM OF THE REVIEW: The review article summarizes recent advancements in lipidomic methodologies from 2019 to 2023 for diagnosing major neurodegenerative diseases, Alzheimer's and Parkinson's, serious non-communicable cardiovascular diseases and cancer, emphasizing the role of lipid level variations, and highlighting the potential of lipidomics data integration with genomics and proteomics to improve disease understanding and innovative prognostic, diagnostic and therapeutic strategies. KEY SCIENTIFIC CONCEPTS OF REVIEW: Clinical lipidomic studies are a promising approach to track and analyze lipid profiles, revealing their crucial roles in various diseases. This lipid-focused research provides insights into disease mechanisms, biomarker identification, and potential therapeutic targets, advancing our understanding and management of conditions such as Alzheimer's Disease, Parkinson's Disease, Cardiovascular Diseases, and specific cancers.


Assuntos
Doença de Alzheimer , Doenças Cardiovasculares , Neoplasias , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Lipídeos/análise , Metabolômica/métodos , Doença de Alzheimer/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Doenças Cardiovasculares/diagnóstico , Doença de Parkinson/diagnóstico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Neoplasias/diagnóstico
20.
Science ; 383(6687): 1092-1095, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38452082

RESUMO

Among vertebrates, the yolk is commonly the only form of nutritional investment offered by the female to the embryo. Some species, however, have developed parental care behaviors associated with specialized food provisioning essential for offspring survival, such as the production of lipidic-rich parental milk in mammals. Here, we show that females of the egg-laying caecilian amphibian Siphonops annulatus provide similarly lipid-rich milk to altricial hatchlings during parental care. We observed that for 2 months, S. annulatus babies ingested milk released through the maternal vent seemingly in response to tactile and acoustic stimulation by the babies. The milk, composed mainly of lipids and carbohydrates, originates from the maternal oviduct epithelium's hypertrophied glands. Our data suggest lactation in this oviparous nonmammalian species and expand the knowledge of parental care and communication in caecilians.


Assuntos
Anfíbios , Lactação , Leite , Oviparidade , Animais , Feminino , Anfíbios/fisiologia , Leite/química , Oviductos/citologia , Oviductos/fisiologia , Oviparidade/fisiologia , Tato , Lipídeos/análise
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