RESUMEN
Partial remission (PR) occurs in only half of people with new-onset type 1 diabetes (T1D) and corresponds to a transient period characterized by low daily insulin needs, low glycemic fluctuations and increased endogenous insulin secretion. While identification of people with newly-onset T1D and significant residual beta-cell function may foster patient-specific interventions, reliable predictive biomarkers of PR occurrence currently lack. We analyzed the plasma of children with new-onset T1D to identify biomarkers present at diagnosis that predicted PR at 3 months post-diagnosis. We first performed an extensive shotgun proteomic analysis using Liquid Chromatography-Tandem-Mass-Spectrometry (LCMS/MS) on the plasma of 16 children with new-onset T1D and quantified 98 proteins significantly correlating with Insulin-Dose Adjusted glycated hemoglobin A1c score (IDAA1C). We next applied a series of both qualitative and statistical filters and selected protein candidates that were associated to pathophysiological mechanisms related to T1D. Finally, we translationally verified several of the candidates using single-shot targeted proteomic (PRM method) on raw plasma. Taken together, we identified plasma biomarkers present at diagnosis that may predict the occurrence of PR in a single mass-spectrometry run. We believe that the identification of new predictive biomarkers of PR and ß-cell function is key to stratify people with new-onset T1D for ß-cell preservation therapies.
Asunto(s)
Biomarcadores , Diabetes Mellitus Tipo 1 , Proteómica , Humanos , Diabetes Mellitus Tipo 1/sangre , Biomarcadores/sangre , Niño , Proteómica/métodos , Masculino , Femenino , Adolescente , Preescolar , Espectrometría de Masas en Tándem , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Cromatografía Liquida , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/metabolismo , Inducción de Remisión , Insulina/sangreRESUMEN
Shortening of telomere length (TL) is correlated with many age-related disorders and is a hallmark of biological aging. This study used proteome-wide Mendelian randomization to identify the protein biomarkers associated with telomere length. Protein quantitative trait loci (pQTL) were derived from two studies, the deCODE Health study (4907 plasma proteins) and the UK Biobank Pharma Proteomics Project (2923 plasma proteins). Summary data from genome-wide association studies (GWAS) for TL were obtained from the UK Biobank (472,174 cases) and GWAS Catalog (418,401 cases). The association between proteins and TL was further assessed using colocalization and summary data-based Mendelian randomization (SMR) analyses. The protein-protein network, druggability assessment, and phenome-wide MR were used to further evaluate the potential biological effects, druggability, and safety of the target proteins. Proteome-wide MR analysis identified 22 plasma proteins that were causally associated with telomere length. Five of these proteins (APOE, SPRED2, MAX, RALY, and PSMB1) had the highest evidence of association with TL and should be prioritized. This study revealed telomere length-related protein biomarkers, providing new insights into the development of new treatment targets for chronic diseases and anti-aging intervention strategies.
Asunto(s)
Biomarcadores , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Proteómica , Sitios de Carácter Cuantitativo , Humanos , Biomarcadores/sangre , Proteómica/métodos , Homeostasis del Telómero , Telómero/metabolismo , Telómero/genética , Proteoma/metabolismo , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Acortamiento del TelómeroRESUMEN
Plasma protein biomarkers have been considered promising tools for diagnosing dementia subtypes due to their low variability, cost-effectiveness, and minimal invasiveness in diagnostic procedures. Machine learning (ML) methods have been applied to enhance accuracy of the biomarker discovery. However, previous ML-based studies often overlook interactions between proteins, which are crucial in complex disorders like dementia. While protein-protein interactions (PPIs) have been used in network models, these models often fail to fully capture the diverse properties of PPIs due to their local awareness. This drawback increases the chance of neglecting critical components and magnifying the impact of noisy interactions. In this study, we propose a novel graph-based ML model for dementia subtype diagnosis, the graph propagational network (GPN). By propagating the independent effect of plasma proteins on PPI network, the GPN extracts the globally interactive effects between proteins. Experimental results showed that the interactive effect between proteins yielded to further clarify the differences between dementia subtype groups and contributed to the performance improvement where the GPN outperformed existing methods by 10.4% on average.
Asunto(s)
Biomarcadores , Proteínas Sanguíneas , Demencia , Aprendizaje Automático , Mapas de Interacción de Proteínas , Humanos , Demencia/metabolismo , Demencia/diagnóstico , Proteínas Sanguíneas/metabolismo , Mapeo de Interacción de Proteínas/métodos , Algoritmos , Biología Computacional/métodosRESUMEN
BACKGROUND: Migraine is a highly prevalent and complex neurovascular disease. However, the currently available therapeutic drugs often fall to adequately meet clinical needs due to limited effectiveness and numerous undesirable side effects. This study aims to identify putative novel targets for migraine treatment through proteome-wide Mendelian randomization (MR). METHODS: We utilized MR to estimate the causal effects of plasma proteins on migraine and its two subtypes, migraine with aura (MA) and without aura (MO). This analysis integrated plasma protein quantitative trait loci (pQTL) data with genome-wide association studies (GWAS) findings for these migraine phenotypes. Moreover, we conducted a phenome-wide MR assessment, enrichment analysis, protein-protein interaction networks construction, and mediation MR analysis to further validate the pharmaceutical potential of the identified protein targets. RESULTS: We identified 35 protein targets for migraine and its subtypes (p < 8.04 × 10-6), with prioritized targets showing minimal side effects. Phenome-wide MR identified novel protein targets-FCAR, UBE2L6, LATS1, PDCD1LG2, and MMP3-that have no major disease side effects and interacted with current acute migraine medication targets. Additionally, MMP3, PDCD1LG2, and HBQ1 interacted with current preventive migraine medication targets. The causal effects of plasma protein on migraine were partly mediated by plasma metabolites (proportion of mediation from 3.8% to 21.0%). CONCLUSIONS: A set of potential protein targets for migraine and its subtypes were identified. These proteins showed rare side effects and were responsible for biological mechanisms involved in migraine pathogenesis, indicating priority for the development of migraine treatments.
Asunto(s)
Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Proteoma , Sitios de Carácter Cuantitativo , Humanos , Proteoma/efectos de los fármacos , Trastornos Migrañosos/genética , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/sangre , Mapas de Interacción de Proteínas/genética , Migraña con Aura/genética , Migraña con Aura/tratamiento farmacológico , Migraña con Aura/sangre , Migraña sin Aura/genética , Migraña sin Aura/tratamiento farmacológico , Migraña sin Aura/sangre , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismoRESUMEN
In this study, a comprehensive investigation was undertaken to elucidate a simple triazole compound, 5-phenyl-1-(p-tolyl)-1â¯H-1,2,3-triazole (PPTT), its interactions with high-abundant proteins and identification of low-abundant proteins by serum proteomics. Employing a combination of spectroscopic techniques and computational chemistry, the interactions between PPTT and three high-abundance blood globular proteins, namely human serum albumin (HSA), human immunoglobulin G (HIgG), and hemoglobin (BHb), were explored, thereby ascertaining their binding constants and thermodynamic parameters at the molecular level. Subsequently, based on the differential proteomics, utilizing two-dimensional gel electrophoresis (2-DE) in conjunction with matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS), the research team isolated and identified differentially expressed low-abundance proteins in human blood serum samples following exposure to PPTT. The results showed that there were twenty highly expressed proteins identified from blood serum samples intervened by PPTT. Combining bioinformatics techniques, these proteins were classified, providing preliminary insights like preproprotein or precursors inhibiting the activity of elastase, defending and regulating the immune system, carrying lipid, and other functions into their biological functionalities. One of the differential proteins, apolipoprotein A-1 (ApoA-1) protein, was selected as a possible target to explore the mechanism of action of PPTT intervention on the related signaling pathways involved in human hepatocellular carcinomas(Hep G2) cells. These research findings offer scientifically sound guidance for further in-depth exploration, development, and application of the 1,2,3-triazole compound.
Asunto(s)
Proteínas Sanguíneas , Proteómica , Triazoles , Humanos , Triazoles/química , Proteómica/métodos , Proteínas Sanguíneas/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Inmunoglobulina G/sangre , Electroforesis en Gel Bidimensional/métodos , Albúmina Sérica Humana/metabolismo , Unión Proteica , Hemoglobinas/metabolismo , TermodinámicaRESUMEN
OBJECTIVE: This study is aimed to investigate the causal relationship between plasma proteins and oral cancer risk using two-sample MR (Mendelian randomization). METHODS: Summary-level GWAS (genome-wide association study) data on plasma protein levels (4,907 proteins) and oral cancer (6,034 cases, 6,585 controls) of European ancestry were utilized. SNPs (single nucleotide polymorphisms) associated with proteins at genome-wide significance were selected as instrumental variables. Multiple MR methods including IVW (inverse-variance weighted), MR-Egger, weighted median, simple mode and weighted mode were applied to estimate causal effects. Sensitivity analyses were conducted. RESULTS: Eight plasma proteins (CCDC167, MID2, NDRG4, PEAR1, PIAS4, RCAN1, SAMHD1 and TNMD) were identified to have significant causal associations with oral cancer risk. NDRG4, RCAN1, SAMHD1 and TNMD were associated with increased oral cancer risk while PEAR1 was associated with decreased risk. The causal estimates were consistent across different methods. Sensitivity analyses indicated the results were robust without significant heterogeneity or horizontal pleiotropy. Multivariable MR adjusting for smoking, alcohol intake and periodontal disease showed CCDC167, MID2, NDRG4, PEAR1, PIAS4 and SAMHD1 still had direct effects on oral cancer. CONCLUSION: This two-sample MR study provides evidence for potentially causal effects of several plasma proteins on oral cancer risk. The identified proteins may serve as biomarkers and shed light on biological mechanisms underlying oral carcinogenesis. Further research is warranted to validate and extend these findings.
Asunto(s)
Proteínas Sanguíneas , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Neoplasias de la Boca , Polimorfismo de Nucleótido Simple , Humanos , Neoplasias de la Boca/genética , Neoplasias de la Boca/sangre , Proteínas Sanguíneas/genética , Incidencia , Causalidad , Factores de RiesgoRESUMEN
Protein electrophoresis (PEP) is an important tool in mammals to characterize specific dysproteinemias and detect acute and chronic inflammatory responses. In reptiles, PEP is the gold standard method for globulin fraction determination and albumin measurement. In this study, preliminary reference intervals were established for serum PEP in 22 clinically healthy adult Roti Island snake-necked turtles (Chelodina mccordi), a critically endangered species, kept in captivity and sampled over two monsoon seasons. The species has a prominent prealbumin fraction and ß-globulins were the dominant globulin fraction. Significant differences between females and males were found in prealbumin (P < 0.01), albumin (P = 0.02), α1-globulin (P = 0.05) and γ-globulin (P = 0.01). Gravid females had significantly lower total protein (P < 0.01), prealbumin (P < 0.01), albumin (P < 0.01) and albumin:globulin ratio (P = 0.01). These preliminary reference intervals should aid in clinical investigation in this species as well as further research studies seeking to understand the application of PEP in reptilian species.
Asunto(s)
Proteínas Sanguíneas , Tortugas , Animales , Tortugas/sangre , Proteínas Sanguíneas/análisis , Femenino , Valores de Referencia , Masculino , Electroforesis de las Proteínas Sanguíneas/veterinaria , Electroforesis de las Proteínas Sanguíneas/métodos , Animales de Zoológico/sangreRESUMEN
Leopard sharks (Triakis semifasciata) are temperate, Eastern Pacific elasmobranchs popular in public aquariums. Blood analysis is commonly used for assessing animal health, yet reference values have not been established for this species. This study analyzed T. semifasciata population data to characterize blood reference values for a collection of T. semifasciata housed at a public aquarium. Twenty-one captive leopard sharks were sampled. Blood was collected during annual health examinations from sedated animals. After collection, blood samples were anticoagulated with lithium heparin, and hematocrit and plasma biochemistry values were analyzed. The minimum-maximum ranges were hematocrit 11-31%, buffy coat 1-2%, glucose 4.94-9.38 mM/L, sodium 244-272 mM/L, potassium 3.7-5.5 mM/L, chloride 214-246 mM/L, aspartate aminotransferase 5-31 U/L, creatine kinase 36-1,136 U/L, calcium 3.65-3.95 mM/L, phosphorus 1.13-2.23 mM/L, total protein 21-38 g/L, and total CO2 12-18 mM/L. The values identified will contribute to a better understanding of captive leopard shark physiology and to improved veterinary care for captive leopard sharks. Further research can examine the validity of machines like the Vetscan VS2, which will expand the resources available to care professionals.
Asunto(s)
Animales de Zoológico , Análisis Químico de la Sangre , Tiburones , Animales , Valores de Referencia , Tiburones/sangre , Animales de Zoológico/sangre , Femenino , Análisis Químico de la Sangre/veterinaria , Masculino , Hematócrito/veterinaria , Glucemia/análisis , Pruebas Hematológicas/veterinaria , Proteínas Sanguíneas/análisisRESUMEN
OBJECTIVE: The study compared the impact of unfractionated heparin (UFH) administered via two routes (infusion and subcutaneous injection) on heparin-binding protein (HBP) and plasminogen activator inhibitor-1 (PAI-1) levels in critically ill sepsis patients. PATIENTS AND METHODS: Forty critically ill sepsis patients were randomly assigned to receive either a low-dose intravenous infusion of UFH (500 units/hour) or subcutaneous UFH (5,000 units/8 hours) for seven days. HBP and PAI-1 were measured at baseline and on days one, two, and seven. RESULTS: Intravenous administration of UFH showed a significant reduction in percentage change of HBP compared to subcutaneous administration on days one [(-35% vs. -13%, p = 0.03*) (*indicates a significant result *p < 0.05, relative to the subcutaneous group)] and seven (-62% vs. -39%, p = 0.02*). Also, the percentage change of PAI-1 was significantly reduced in the infusion group compared to the subcutaneous group on days one (-28% vs. -3%, p = 0.008*), two (-42% vs. -3%, p = 0.001*), and seven (-62% vs. 27%, p = 0.001*), respectively. Furthermore, a significant improvement in the 14-day survival was observed in the infusion group compared to the subcutaneous group (p = 0.008*). CONCLUSIONS: Intravenous infusion was the route of choice for UFH administration in critically ill septic patients, with a promising effect on HBP, PAI-1, and survival.
Asunto(s)
Enfermedad Crítica , Heparina , Inhibidor 1 de Activador Plasminogénico , Sepsis , Humanos , Heparina/administración & dosificación , Infusiones Intravenosas , Sepsis/tratamiento farmacológico , Inyecciones Subcutáneas , Masculino , Femenino , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/administración & dosificación , Inhibidor 1 de Activador Plasminogénico/metabolismo , Proteínas Sanguíneas/metabolismo , Anciano , Péptidos Catiónicos Antimicrobianos/administración & dosificación , Anticoagulantes/administración & dosificaciónRESUMEN
OBJECTIVES: The Dietary Approaches to Stop Hypertension (DASH) diet reduces blood pressure, but the mechanisms underlying DASH diet-blood pressure relations are not well understood. Proteomic measures may provide insights into the pathophysiological mechanisms through which the DASH diet reduces blood pressure. METHODS: The DASH (1994-1996) and DASH-Sodium (1997-1999) trials were multicenter, randomized-controlled feeding trials. Proteomic profiling was conducted in serum collected at the end of the feeding period (DASH, Nâ=â215; DASH-Sodium, Nâ=â390). Multivariable linear regression models were used to identify interactions between 71 DASH diet-related proteins and changes in systolic and diastolic blood pressure. Estimates were meta-analyzed across both trials. Elastic net models were used to identify proteins that predict changes in blood pressure. RESULTS: Ten significant interactions were identified [systolic blood pressure: seven proteins; diastolic blood pressure: three proteins], which represented nine unique proteins. A high level of renin at the end of the feeding period was associated with greater reductions in diastolic blood pressure in individuals consuming the control than DASH diets. A high level of procollagen c-endopeptidase enhancer 1 (PCOLCE) and collagen triple helix repeat-containing protein 1 (CTHRC1) were associated with greater reductions in systolic blood pressure in individuals consuming the DASH than control diets, and with elevations in systolic blood pressure in individuals consuming the control diets (P for interaction for all tests < 0.05). Elastic net models identified six additional proteins that predicted change in blood pressure. CONCLUSIONS: Several novel proteins were identified that may provide some insight into the relationship between the DASH diet and blood pressure.
Asunto(s)
Presión Sanguínea , Proteínas Sanguíneas , Enfoques Dietéticos para Detener la Hipertensión , Hipertensión , Humanos , Masculino , Persona de Mediana Edad , Femenino , Hipertensión/dietoterapia , Hipertensión/sangre , Proteínas Sanguíneas/metabolismo , Adulto , Dieta Hiposódica , Proteómica/métodosRESUMEN
The kidney tubules constitute two-thirds of the cells of the kidney and account for the majority of the organ's metabolic energy expenditure. Acute tubular injury (ATI) is observed across various types of kidney diseases and may significantly contribute to progression to kidney failure. Non-invasive biomarkers of ATI may allow for early detection and drug development. Using the SomaScan proteomics platform on 434 patients with biopsy-confirmed kidney disease, we here identify plasma biomarkers associated with ATI severity. We employ regional transcriptomics and proteomics, single-cell RNA sequencing, and pathway analysis to explore biomarker protein and gene expression and enriched biological pathways. Additionally, we examine ATI biomarker associations with acute kidney injury (AKI) in the Kidney Precision Medicine Project (KPMP) (n = 44), the Atherosclerosis Risk in Communities (ARIC) study (n = 4610), and the COVID-19 Host Response and Clinical Outcomes (CHROME) study (n = 268). Our findings indicate 156 plasma proteins significantly linked to ATI with osteopontin, macrophage mannose receptor 1, and tenascin C showing the strongest associations. Pathway analysis highlight immune regulation and organelle stress responses in ATI pathogenesis.
Asunto(s)
Lesión Renal Aguda , Biomarcadores , COVID-19 , Osteopontina , Proteómica , Humanos , Lesión Renal Aguda/sangre , Proteómica/métodos , Masculino , Biomarcadores/sangre , Femenino , Persona de Mediana Edad , COVID-19/sangre , Osteopontina/sangre , Tenascina/sangre , Tenascina/genética , Tenascina/metabolismo , Túbulos Renales/metabolismo , Túbulos Renales/patología , Anciano , Adulto , SARS-CoV-2 , Análisis de la Célula Individual , Proteínas Sanguíneas/metabolismoRESUMEN
Neonatal sepsis is a major global health challenge, leading to significant morbidity and mortality in newborns. The search for precise biomarkers for its early prediction in clinical settings has been ongoing, with heparin-binding protein (HBP) emerging as a promising candidate. Originating from granules in neutrophils, HBP is released into the bloodstream in response to infection and plays a pivotal role in the body's inflammatory response. Its significance extends beyond its inflammatory origins; research indicates dynamic changes in HBP levels are strongly linked to reduce in-hospital mortality, offering a prognostic advantage over existing biomarkers. Furthermore, HBP has demonstrated considerable clinical utility in the early diagnosis and stratification of neonatal sepsis, suggesting its potential as a reliable blood marker for early prediction of the disease and its severity. Its application may extend to guiding the judicious use of antibiotics in treating newborns, addressing a critical aspect of neonatal care. Despite these encouraging results, the precise clinical utility of HBP for diagnosing and treating sepsis in neonates still demands further clarification through extensive research. This review delves into the current scientific understanding of HBP's contribution to diagnosing, prognosticating, and treating neonatal sepsis, while considering its future clinical applications.
Asunto(s)
Péptidos Catiónicos Antimicrobianos , Biomarcadores , Proteínas Sanguíneas , Sepsis Neonatal , Humanos , Sepsis Neonatal/diagnóstico , Recién Nacido , Biomarcadores/sangre , Proteínas Sanguíneas/metabolismo , Péptidos Catiónicos Antimicrobianos/metabolismo , Péptidos Catiónicos Antimicrobianos/sangre , Pronóstico , Antibacterianos/uso terapéutico , Neutrófilos/metabolismoRESUMEN
BACKGROUND: The severe course of COVID-19 causes cardiovascular injuries, although the mechanisms involved are still not fully recognized, linked, and understood. Their characterization is of great importance with the establishment of the conception of post-acute sequelae of COVID-19, referred to as long COVID, where blood clotting and endothelial abnormalities are believed to be the key pathomechanisms driving circulatory system impairment. METHODS: The presented study investigates temporal changes in plasma proteins in COVID-19 patients during hospitalization due to SARS-CoV-2 infection and six months after recovery by targeted SureQuant acquisition using PQ500 panel. RESULTS: In total, we identified 167 proteins that were differentially regulated between follow-up and hospitalization, which functionally aggregated into immune system activation, complement and coagulation cascades, interleukins signalling, platelet activation, and extracellular matrix organization. Furthermore, we found that temporal quantitative changes in acute phase proteins correlate with selected clinical characteristics of COVID-19 patients. CONCLUSIONS: In-depth targeted proteome investigation evidenced substantial changes in plasma protein composition of patients during and recovering from COVID-19, evidencing a wide range of functional pathways induced by SARS-CoV-2 infection. In addition, we show that a subset of acute phase proteins, clotting cascade regulators and lipoproteins could have clinical value as potential predictors of long-term cardiovascular events in COVID-19 convalescents.
Asunto(s)
Proteínas Sanguíneas , COVID-19 , Proteoma , SARS-CoV-2 , Humanos , COVID-19/sangre , Proteoma/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/análisis , Anciano , Adulto , Proteómica/métodos , Proteínas de Fase Aguda/metabolismoRESUMEN
BACKGROUND: Systemic inflammation stands as a pivotal factor tightly interwoven with the progression of COVID-19. This study endeavors to elucidate the significance of three key inflammatory molecules, that is, heparin-binding protein (HBP), interleukin-6 (IL-6), and C-reactive protein (CRP), in assessing the severity and prognostic implications of COVID-19. METHODS: The demographic, clinical, and laboratory data were retrospectively collected from a cohort of 214 adult patients diagnosed with COVID-19. Patients were divided into two groups: nonsevere (n = 93; 43.5%) and severe (n = 121; 56.5%). Additionally, based on their organ function, patients were categorized into nonorgan failure (n = 137) and organ failure (n = 77) groups. The levels of inflammation-related cytokines were then compared among these defined groups. RESULTS: The severe group was characterized by a higher proportion of males, older age, and longer hospital stays compared to nonsevere cases. Additionally, severe cases exhibited a higher prevalence of underlying diseases and organ failure. Statistical analysis revealed significantly elevated levels of HBP, IL-6, and CRP in the severe group. HBP, IL-6, and CRP were identified as independent risk factors for severe COVID-19. Furthermore, a combined assessment of these biomarkers demonstrated superior diagnostic sensitivity (85.10%) and specificity (95.70%) for predicting COVID-19 severity. A positive relationship between elevated HBP, IL-6, and CRP levels and impaired organ function was also observed. The predictive efficiency significantly increased (hazard ratio = 3.631, log-rank p = 0.003) when two or more of them were combinedly used. Notably, elevated levels of HBP, IL-6, and CRP were associated with an increased risk of mortality. CONCLUSIONS: In conclusion, the combined assessment of HBP, IL-6, and CRP offers enhanced accuracy and specificity in predicting the severity, organ failure, and mortality risk associated with COVID-19.
Asunto(s)
Biomarcadores , Proteína C-Reactiva , COVID-19 , Interleucina-6 , Índice de Severidad de la Enfermedad , Humanos , COVID-19/sangre , COVID-19/diagnóstico , COVID-19/epidemiología , Masculino , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Femenino , Estudios Retrospectivos , Interleucina-6/sangre , Persona de Mediana Edad , Anciano , Biomarcadores/sangre , Pronóstico , SARS-CoV-2 , Adulto , Proteínas Sanguíneas , Proteínas Portadoras/sangre , Valor Predictivo de las Pruebas , Péptidos Catiónicos AntimicrobianosRESUMEN
The translation of silver-based nanotechnology 'from bench to bedside' requires a deep understanding of the molecular aspects of its biological action, which remains controversial at low concentrations and non-spherical morphologies. Here, we present a hemocompatibility approach based on the effect of the distinctive electronic charge distribution in silver nanoparticles (nanosilver) on blood components. According to spectroscopic, volumetric, microscopic, dynamic light scattering measurements, pro-coagulant activity tests, and cellular inspection, we determine that at extremely low nanosilver concentrations (0.125-2.5µg ml-1), there is a relevant interaction effect on the serum albumin and red blood cells (RBCs). This explanation has its origin in the surface charge distribution of nanosilver particles and their electron-mediated energy transfer mechanism. Prism-shaped nanoparticles, with anisotropic charge distributions, act at the surface level, generating a compaction of the native protein molecule. In contrast, the spherical nanosilver particle, by exhibiting isotropic surface charge, generates a polar environment comparable to the solvent. Both morphologies induce aggregation at NPs/bovine serum albumin ≈ 0.044 molar ratio values without altering the coagulation cascade tests; however, the spherical-shaped nanosilver exerts a negative impact on RBCs. Overall, our results suggest that the electron distributions of nanosilver particles, even at extremely low concentrations, are a critical factor influencing the molecular structure of blood proteins' and RBCs' membranes. Isotropic forms of nanosilver should be considered with caution, as they are not always the least harmful.
Asunto(s)
Eritrocitos , Nanopartículas del Metal , Albúmina Sérica Bovina , Plata , Plata/química , Nanopartículas del Metal/química , Eritrocitos/metabolismo , Eritrocitos/química , Humanos , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , Propiedades de Superficie , Animales , Bovinos , Coagulación Sanguínea/efectos de los fármacos , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/química , Ensayo de MaterialesRESUMEN
Retinal artery occlusion (RAO), which is positively correlated with acute ischemic stroke (IS) and results in severe visual impairment, lacks effective intervention drugs. This study aims to perform integrated analysis using UK Biobank plasma proteome data of RAO and IS to identify potential targets and preventive drugs. A total of 7191 participants (22 RAO patients, 1457 IS patients, 8 individuals with both RAO and IS, and 5704 healthy age-gender-matched controls) were included in this study. Unique 1461 protein expression profiles of RAO, IS, and the combined data set, extracted from UK Biobank Plasma proteomics projects, were analyzed using both differential expression analysis and elastic network regression (Enet) methods to identify shared key proteins. Subsequent analyses, including single cell type expression assessment, pathway enrichment, and druggability analysis, were conducted for verifying shared key proteins and discovery of new drugs. Five proteins were found to be shared among the samples, with all of them showing upregulation. Notably, adhesion G-protein coupled receptor G1 (ADGRG1) exhibited high expression in glial cells of the brain and eye tissues. Gene set enrichment analysis revealed pathways associated with lipid metabolism and vascular regulation and inflammation. Druggability analysis unveiled 15 drug candidates targeting ADGRG1, which demonstrated protective effects against RAO, especially troglitazone (-8.5 kcal/mol). Our study identified novel risk proteins and therapeutic drugs associated with the rare disease RAO, providing valuable insights into potential intervention strategies.
Asunto(s)
Bancos de Muestras Biológicas , Proteómica , Oclusión de la Arteria Retiniana , Humanos , Proteómica/métodos , Masculino , Femenino , Reino Unido , Oclusión de la Arteria Retiniana/tratamiento farmacológico , Oclusión de la Arteria Retiniana/metabolismo , Oclusión de la Arteria Retiniana/sangre , Oclusión de la Arteria Retiniana/genética , Persona de Mediana Edad , Anciano , Proteoma/metabolismo , Proteoma/análisis , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/metabolismo , Estudios de Casos y Controles , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/análisis , Biobanco del Reino UnidoRESUMEN
Leptospirosis, a notifiable endemic disease in Malaysia, has higher mortality rates than regional dengue fever. Diverse clinical symptoms and limited diagnostic methods complicate leptospirosis diagnosis. The demand for accurate biomarker-based diagnostics is increasing. This study investigated the plasma proteome of leptospirosis patients with leptospiraemia and seroconversion compared with dengue patients and healthy subjects using isobaric tags for relative and absolute quantitation (iTRAQ)-mass spectrometry (MS). The iTRAQ analysis identified a total of 450 proteins, which were refined to a list of 290 proteins through a series of exclusion criteria. Differential expression in the plasma proteome of leptospirosis patients compared to the control groups identified 11 proteins, which are apolipoprotein A-II (APOA2), C-reactive protein (CRP), fermitin family homolog 3 (FERMT3), leucine-rich alpha-2-glycoprotein 1 (LRG1), lipopolysaccharide-binding protein (LBP), myosin-9 (MYH9), platelet basic protein (PPBP), platelet factor 4 (PF4), profilin-1 (PFN1), serum amyloid A-1 protein (SAA1), and thrombospondin-1 (THBS1). Following a study on a verification cohort, a panel of eight plasma protein biomarkers was identified for potential leptospirosis diagnosis: CRP, LRG1, LBP, MYH9, PPBP, PF4, SAA1, and THBS1. In conclusion, a panel of eight protein biomarkers offers a promising approach for leptospirosis diagnosis, addressing the limitations of the "one disease, one biomarker" concept.
Asunto(s)
Biomarcadores , Proteínas Sanguíneas , Leptospirosis , Humanos , Leptospirosis/diagnóstico , Leptospirosis/sangre , Biomarcadores/sangre , Proteínas Sanguíneas/análisis , Masculino , Femenino , Adulto , Proteína Amiloide A Sérica/análisis , Glicoproteínas de Membrana/sangre , Proteínas de Fase Aguda/análisis , Proteína C-Reactiva/análisis , Proteínas Portadoras/sangre , Dengue/diagnóstico , Dengue/sangre , Proteoma/análisis , Proteínas de la Membrana/sangre , Proteómica/métodos , Persona de Mediana Edad , Factor Plaquetario 4/sangre , Trombospondina 1/sangre , Estudios de Casos y Controles , GlicoproteínasRESUMEN
Given recent technological advances in proteomics, it is now possible to quantify plasma proteomes in large cohorts of patients to screen for biomarkers and to guide the early diagnosis and treatment of depression. Here we used CatBoost machine learning to model and discover biomarkers of depression in UK Biobank data sets (depression n = 4,479, healthy control n = 19,821). CatBoost was employed for model construction, with Shapley Additive Explanations (SHAP) being utilized to interpret the resulting model. Model performance was corroborated through 5-fold cross-validation, and its diagnostic efficacy was evaluated based on the area under the receiver operating characteristic (AUC) curve. A total of 45 depression-related proteins were screened based on the top 20 important features output by the CatBoost model in six data sets. Of the nine diagnostic models for depression, the performance of the traditional risk factor model was improved after the addition of proteomic data, with the best model having an average AUC of 0.764 in the test sets. KEGG pathway analysis of 45 screened proteins showed that the most significant pathway involved was the cytokine-cytokine receptor interaction. It is feasible to explore diagnostic biomarkers of depression using data-driven machine learning methods and large-scale data sets, although the results require validation.
Asunto(s)
Biomarcadores , Depresión , Aprendizaje Automático , Proteómica , Humanos , Biomarcadores/sangre , Proteómica/métodos , Depresión/sangre , Depresión/diagnóstico , Algoritmos , Curva ROC , Área Bajo la Curva , Proteoma/análisis , Proteoma/metabolismo , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/metabolismo , Masculino , FemeninoRESUMEN
Polyhexamethylene guanidine (PHMG) is a positively charged polymer used as a disinfectant that kills microbes but can cause pulmonary fibrosis if inhaled. After the long-term risks were confirmed in South Korea, it became crucial to measure toxicity through diverse surrogate biomarkers, not only proteins, especially after these hazardous chemicals had cleared from the body. These biomarkers, identified by their biological functions rather than simple numerical calculations, effectively explained the imbalance of pulmonary surfactant caused by fibrosis from PHMG exposure. These long-term studies on children exposed to PHMG has shown that blood protein indicators, primarily related to apolipoproteins and extracellular matrix, can distinguish the degree of exposure to humidifier disinfectants (HDs). We defined the extreme gradient boosting models and computed reflection scores based on just ten selected proteins, which were also verified in adult women exposed to HD. The reflection scores successfully discriminated between the HD-exposed and unexposed groups in both children and adult females (AUROC: 0.957 and 0.974, respectively) and had a strong negative correlation with lung function indicators. Even after an average of more than 10 years, blood is still considered a meaningful specimen for assessing the impact of environmental exposure to toxic substances, with proteins providing in identifying the pathological severity of such conditions.
Asunto(s)
Aerosoles , Proteínas Sanguíneas , Guanidinas , Humanos , Guanidinas/toxicidad , Guanidinas/química , Femenino , Adulto , Proteínas Sanguíneas/análisis , Lesión Pulmonar/inducido químicamente , Biomarcadores/sangre , Desinfectantes/toxicidad , Niño , Humidificadores , Exposición por Inhalación/efectos adversosRESUMEN
INTRODUCTION: Depressive symptoms are a common concomitant of cerebral small vessel disease (CSVD), of which pathogenesis requires more study. White matter microstructural abnormalities and proteomic alternation have been widely reported regarding depression in the elderly with CSVD. Exploring the relationship between cerebral white matter microstructural alterations and serum proteins may complete the explanation of molecular mechanisms for the findings from neuroimaging research of CSVD combined with depressive symptoms. METHODS: An untargeted proteomics approach based on mass spectrometry was used to obtain serum proteomic profiles, which were clustered into co-expression protein modules. White matter microstructural integrity was measured using the FMRIB Software Library (FSL) and MATLAB to analyze diffusion tensor imaging (DTI) data and calculate the differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) for 50 regions of interest (ROI). Integrating the proteome with the DTI results, weighted gene co-expression analysis (WGCNA) was used to identify protein modules related to white matter microstructural alterations, and the proteins of the corresponding modules were analyzed for functional enrichment through bioinformatics techniques. RESULTS: DTI measurements were analCerebral small vessel disease (CSVD); Depression; Diffusion tensor imaging (DTI); Proteomics; Inflammationyzed between individuals with CSVD and depressive symptoms (CSVD+D) (n = 24) and those without depressive symptoms (CSVD-D) (n = 35). Results showed an overall increase in MD, AD, and RD within the left hemisphere of the CSVD+D group, suggesting widespread loss of white matter integrity and axonal demyelination, including left superior longitudinal fasciculus (SLF), left posterior corona radiata (PCR) and right external capsule (EC). We identified two protein modules associated with DTI diffusivity, and functional enrichment analyses revealed that complement and coagulation cascades and immune responses participate in the alternation of white matter microstructure in the CSVD+D group. CONCLUSION: The results suggested immune- and inflammation-related mechanism was associated with white matter microstructure changes in CSVD with depressive symptoms.