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1.
J Proteome Res ; 2024 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-38456420

RESUMEN

A computational analysis of mass spectrometry data was performed to uncover alternative splicing derived protein variants across chambers of the human heart. Evidence for 216 non-canonical isoforms was apparent in the atrium and the ventricle, including 52 isoforms not documented on SwissProt and recovered using an RNA sequencing derived database. Among non-canonical isoforms, 29 show signs of regulation based on statistically significant preferences in tissue usage, including a ventricular enriched protein isoform of tensin-1 (TNS1) and an atrium-enriched PDZ and LIM Domain 3 (PDLIM3) isoform 2 (PDLIM3-2/ALP-H). Examined variant regions that differ between alternative and canonical isoforms are highly enriched with intrinsically disordered regions. Moreover, over two-thirds of such regions are predicted to function in protein binding and RNA binding. The analysis here lends further credence to the notion that alternative splicing diversifies the proteome by rewiring intrinsically disordered regions, which are increasingly recognized to play important roles in the generation of biological function from protein sequences.

2.
Curr Opin Pulm Med ; 30(2): 185-194, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-37851380

RESUMEN

PURPOSE OF REVIEW: There has been a rapid increase in silicosis cases, particularly related to artificial stone. The key to management is avoidance of silica exposure. Despite this, many develop progressive disease and there are no routinely recommended treatments. This review provides a summary of the literature pertaining to pharmacological therapies for silicosis and examines the plausibility of success of such treatments given the disease pathogenesis. RECENT FINDINGS: In-vitro and in-vivo models demonstrate potential efficacy for drugs, which target inflammasomes, cytokines, effector cells, fibrosis, autophagy, and oxidation. SUMMARY: There is some evidence for potential therapeutic targets in silicosis but limited translation into human studies. Treatment of silicosis likely requires a multimodal approach, and there is considerable cross-talk between pathways; agents that modulate both inflammation, fibrosis, autophagy, and ROS production are likely to be most efficacious.


Asunto(s)
Dióxido de Silicio , Silicosis , Humanos , Fibrosis , Autofagia , Citocinas
3.
J Infect Dis ; 2023 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-38060822

RESUMEN

BACKGROUND: Excessive pulmonary inflammation and damage are characteristic features of severe influenza virus infections. LAT8881 is a synthetic, 16 amino acid cyclic peptide form of a naturally occurring C-terminal fragment of human growth hormone with therapeutic efficacy against influenza. Shorter, linear peptides are typically easier to manufacture and formulate for delivery than larger cyclic peptides. A 6 amino acid linear peptide fragment of LAT8881, LAT9997, was investigated as a potential influenza therapy. METHODS: LAT9997 was evaluated for its potential to limit disease in a preclinical mouse model of severe influenza infection. RESULTS: Intranasal treatment of mice with either LAT8881 or LAT9997 from day 1 following influenza infection significantly improved survival outcomes. Initiating LAT9997 treatment at the onset of severe disease, also significantly improved disease severity. Greater disease resistance in LAT9997-treated mice correlated with reduced lung immunopathology, damage markers, vascular leak, and epithelial cell death. Treatment reduced viral loads, cytokines, and neutrophil infiltration in the airways, yet maintained protective alveolar macrophages in a dose-dependent manner. Sequential trimming of N- and C-terminal amino acids from LAT9997 revealed a structure-activity relationship. CONCLUSIONS: These findings provide preclinical evidence that therapeutic LAT9997 treatment limits viral burden and characteristic features of severe influenza, including hyperinflammation and lung damage.

4.
Am J Respir Cell Mol Biol ; 69(2): 182-196, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37098022

RESUMEN

Asthma is a heterogeneous chronic airway disease with an unmet need for improved therapeutics in uncontrolled severe disease. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor upregulated in asthma. The CaSR agonist, spermine, is also increased in asthmatic airways and contributes to bronchoconstriction. CaSR negative allosteric modulators (NAMs) oppose chronic airway inflammation, remodeling, and hyperresponsiveness in murine and guinea pig asthma models, but whether CaSR NAMs are effective acute bronchodilators compared with standard of care has not yet been established. Furthermore, the ability of different classes of NAMs to inhibit spermine-induced CaSR signaling or methacholine (MCh)-induced airway contraction has not been quantified. Here, we show CaSR NAMs differentially inhibit spermine-induced intracellular calcium mobilization and inositol monophosphate accumulation in HEK293 cells stably expressing the CaSR. NAMs reverse MCh-mediated airway contraction in mouse precision-cut lung slices with similar maximal relaxation compared with the standard treatment, salbutamol. Of note, the bronchodilator effects of CaSR NAMs are maintained under conditions of ß2-adrenergic receptor desensitization when salbutamol efficacy is abolished. Furthermore, overnight treatment with some, but not all, CaSR NAMs prevents MCh-mediated bronchoconstriction. These findings further support the CaSR as a putative drug target and NAMs as alternative or adjunct bronchodilators in asthma.


Asunto(s)
Asma , Broncodilatadores , Ratones , Humanos , Animales , Cobayas , Broncodilatadores/farmacología , Receptores Sensibles al Calcio/agonistas , Receptores Sensibles al Calcio/metabolismo , Células HEK293 , Espermina/uso terapéutico , Asma/tratamiento farmacológico , Asma/metabolismo , Albuterol/farmacología , Cloruro de Metacolina/farmacología
5.
PLoS Comput Biol ; 18(11): e1010702, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36356032

RESUMEN

Protein and mRNA levels correlate only moderately. The availability of proteogenomics data sets with protein and transcript measurements from matching samples is providing new opportunities to assess the degree to which protein levels in a system can be predicted from mRNA information. Here we examined the contributions of input features in protein abundance prediction models. Using large proteogenomics data from 8 cancer types within the Clinical Proteomic Tumor Analysis Consortium (CPTAC) data set, we trained models to predict the abundance of over 13,000 proteins using matching transcriptome data from up to 958 tumor or normal adjacent tissue samples each, and compared predictive performances across algorithms, data set sizes, and input features. Over one-third of proteins (4,648) showed relatively poor predictability (elastic net r ≤ 0.3) from their cognate transcripts. Moreover, we found widespread occurrences where the abundance of a protein is considerably less well explained by its own cognate transcript level than that of one or more trans locus transcripts. The incorporation of additional trans-locus transcript abundance data as input features increasingly improved the ability to predict sample protein abundance. Transcripts that contribute to non-cognate protein abundance primarily involve those encoding known or predicted interaction partners of the protein of interest, including not only large multi-protein complexes as previously shown, but also small stable complexes in the proteome with only one or few stable interacting partners. Network analysis further shows a complex proteome-wide interdependency of protein abundance on the transcript levels of multiple interacting partners. The predictive model analysis here therefore supports that protein-protein interaction including in small protein complexes exert post-transcriptional influence on proteome compositions more broadly than previously recognized. Moreover, the results suggest mRNA and protein co-expression analysis may have utility for finding gene interactions and predicting expression changes in biological systems.


Asunto(s)
Proteoma , Proteómica , Proteoma/metabolismo , Proteómica/métodos , Regulación de la Expresión Génica , Transcriptoma , ARN Mensajero/genética , ARN Mensajero/metabolismo
6.
Am J Respir Cell Mol Biol ; 66(6): 601-611, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35290170

RESUMEN

Silicosis is a multifaceted lung disease, characterized by persistent inflammation and structural remodeling. Despite its poor prognosis, there are no treatments currently available for patients with silicosis. Recent preclinical findings in models of lung fibrosis have suggested a major role for the NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome in silica-driven inflammation and fibrosis. This review outlines the beneficial effects of targeting the NLRP3 inflammasome in in vitro cell experiments and in in vivo animal models, whereby inflammation and fibrosis are abrogated after NLRP3 inflammasome inhibition. Although preclinical evidence is promising, studies that explore NLRP3 inflammasomes in the clinical setting are warranted. In particular, there is still a need to identify biomarkers that may be helpful for the early detection of silicosis and to fully elucidate mechanisms underlying these beneficial effects to further develop or repurpose existing anti-NLRP3 drugs as novel treatments that limit disease progression.


Asunto(s)
Inflamasomas , Silicosis , Animales , Polvo , Fibrosis , Humanos , Inflamación , Proteína con Dominio Pirina 3 de la Familia NLR , Silicosis/tratamiento farmacológico
7.
Circulation ; 143(19): 1874-1890, 2021 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-33682427

RESUMEN

BACKGROUND: Diastolic dysfunction (DD) is associated with the development of heart failure and contributes to the pathogenesis of other cardiac maladies, including atrial fibrillation. Inhibition of histone deacetylases (HDACs) has been shown to prevent DD by enhancing myofibril relaxation. We addressed the therapeutic potential of HDAC inhibition in a model of established DD with preserved ejection fraction. METHODS: Four weeks after uninephrectomy and implantation with deoxycorticosterone acetate pellets, when DD was clearly evident, 1 cohort of mice was administered the clinical-stage HDAC inhibitor ITF2357/Givinostat. Echocardiography, blood pressure measurements, and end point invasive hemodynamic analyses were performed. Myofibril mechanics and intact cardiomyocyte relaxation were assessed ex vivo. Cardiac fibrosis was evaluated by picrosirius red staining and second harmonic generation microscopy of left ventricle (LV) sections, RNA sequencing of LV mRNA, mass spectrometry-based evaluation of decellularized LV biopsies, and atomic force microscopy determination of LV stiffness. Mechanistic studies were performed with primary rat and human cardiac fibroblasts. RESULTS: HDAC inhibition normalized DD without lowering blood pressure in this model of systemic hypertension. In contrast to previous models, myofibril relaxation was unimpaired in uninephrectomy/deoxycorticosterone acetate mice. Furthermore, cardiac fibrosis was not evident in any mouse cohort on the basis of picrosirius red staining or second harmonic generation microscopy. However, mass spectrometry revealed induction in the expression of >100 extracellular matrix proteins in LVs of uninephrectomy/deoxycorticosterone acetate mice, which correlated with profound tissue stiffening based on atomic force microscopy. ITF2357/Givinostat treatment blocked extracellular matrix expansion and LV stiffening. The HDAC inhibitor was subsequently shown to suppress cardiac fibroblast activation, at least in part, by blunting recruitment of the profibrotic chromatin reader protein BRD4 (bromodomain-containing protein 4) to key gene regulatory elements. CONCLUSIONS: These findings demonstrate the potential of HDAC inhibition as a therapeutic intervention to reverse existing DD and establish blockade of extracellular matrix remodeling as a second mechanism by which HDAC inhibitors improve ventricular filling. Our data reveal the existence of pathophysiologically relevant covert or hidden cardiac fibrosis that is below the limit of detection of histochemical stains such as picrosirius red, highlighting the need to evaluate fibrosis of the heart using diverse methodologies.


Asunto(s)
Matriz Extracelular/fisiología , Soplos Cardíacos/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/uso terapéutico , Remodelación Ventricular/fisiología , Animales , Modelos Animales de Enfermedad , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Masculino , Ratones
8.
Am J Physiol Heart Circ Physiol ; 323(3): H538-H558, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35930447

RESUMEN

The risks of heart diseases are significantly modulated by age and sex, but how these factors influence baseline cardiac gene expression remains incompletely understood. Here, we used RNA sequencing and mass spectrometry to compare gene expression in female and male young adult (4 mo) and early aging (20 mo) mouse hearts, identifying thousands of age- and sex-dependent gene expression signatures. Sexually dimorphic cardiac genes are broadly distributed, functioning in mitochondrial metabolism, translation, and other processes. In parallel, we found over 800 genes with differential aging response between male and female, including genes in cAMP and PKA signaling. Analysis of the sex-adjusted aging cardiac transcriptome revealed a widespread remodeling of exon usage patterns that is largely independent from differential gene expression, concomitant with upstream changes in RNA-binding protein and splice factor transcripts. To evaluate the impact of the splicing events on cardiac proteoform composition, we applied an RNA-guided proteomics computational pipeline to analyze the mass spectrometry data and detected hundreds of putative splice variant proteins that have the potential to rewire the cardiac proteome. Taken together, the results here suggest that cardiac aging is associated with 1) widespread sex-biased aging genes and 2) a rewiring of RNA splicing programs, including sex- and age-dependent changes in exon usages and splice patterns that have the potential to influence cardiac protein structure and function. These changes contribute to the emerging evidence for considerable sexual dimorphism in the cardiac aging process that should be considered in the search for disease mechanisms.NEW & NOTEWORTHY Han et al. used proteogenomics to compare male and female mouse hearts at 4 and 20 mo. Sex-biased cardiac genes function in mitochondrial metabolism, translation, autophagy, and other processes. Hundreds of cardiac genes show sex-by-age interactions, that is, sex-biased aging genes. Cardiac aging is accompanied with a remodeling of exon usage in functionally coordinated genes, concomitant with differential expression of RNA-binding proteins and splice factors. These features represent an underinvestigated aspect of cardiac aging that may be relevant to the search for disease mechanisms.


Asunto(s)
Proteogenómica , Envejecimiento/genética , Empalme Alternativo , Animales , Femenino , Masculino , Ratones , Proteogenómica/métodos , Empalme del ARN , Proteínas de Unión al ARN/genética
9.
Am J Physiol Heart Circ Physiol ; 323(4): H797-H817, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-36053749

RESUMEN

Approximately 50% of all heart failure (HF) diagnoses can be classified as HF with preserved ejection fraction (HFpEF). HFpEF is more prevalent in females compared with males, but the underlying mechanisms are unknown. We previously showed that pressure overload (PO) in male felines induces a cardiopulmonary phenotype with essential features of human HFpEF. The goal of this study was to determine if slow progressive PO induces distinct cardiopulmonary phenotypes in females and males in the absence of other pathological stressors. Female and male felines underwent aortic constriction (banding) or sham surgery after baseline echocardiography, pulmonary function testing, and blood sampling. These assessments were repeated at 2 and 4 mo postsurgery to document the effects of slow progressive pressure overload. At 4 mo, invasive hemodynamic studies were also performed. Left ventricle (LV) tissue was collected for histology, myofibril mechanics, extracellular matrix (ECM) mass spectrometry, and single-nucleus RNA sequencing (snRNAseq). The induced pressure overload (PO) was not different between sexes. PO also induced comparable changes in LV wall thickness and myocyte cross-sectional area in both sexes. Both sexes had preserved ejection fraction, but males had a slightly more robust phenotype in hemodynamic and pulmonary parameters. There was no difference in LV fibrosis and ECM composition between banded male and female animals. LV snRNAseq revealed changes in gene programs of individual cell types unique to males and females after PO. Based on these results, both sexes develop cardiopulmonary dysfunction but the phenotype is somewhat less advanced in females.NEW & NOTEWORTHY We performed a comprehensive assessment to evaluate the effects of slow progressive pressure overload on cardiopulmonary function in a large animal model of heart failure with preserved ejection fraction (HFpEF) in males and females. Functional and structural assessments were performed at the organ, tissue, cellular, protein, and transcriptional levels. This is the first study to compare snRNAseq and ECM mass spectrometry of HFpEF myocardium from males and females. The results broaden our understanding of the pathophysiological response of both sexes to pressure overload. Both sexes developed a robust cardiopulmonary phenotype, but the phenotype was equal or a bit less robust in females.


Asunto(s)
Insuficiencia Cardíaca , Animales , Gatos , Modelos Animales de Enfermedad , Femenino , Ventrículos Cardíacos , Humanos , Masculino , Volumen Sistólico/fisiología , Función Ventricular Izquierda/fisiología
10.
J Mol Cell Cardiol ; 154: 92-96, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33549679

RESUMEN

Alternative splicing is prevalent in the heart and implicated in many cardiovascular diseases, but not every alternative transcript is translated and detecting non-canonical isoforms at the protein level remains challenging. Here we show the use of a computation-assisted targeted proteomics workflow to detect protein alternative isoforms in the human heart. We build on a recent strategy to integrate deep RNA-seq and large-scale mass spectrometry data to identify candidate translated isoform peptides. A machine learning approach is then applied to predict their fragmentation patterns and design protein isoform-specific parallel reaction monitoring detection (PRM) assays. As proof-of-principle, we built PRM assays for 29 non-canonical isoform peptides and detected 22 peptides in a human heart lysate. The predictions-aided PRM assays closely mirrored synthetic peptide standards for non-canonical sequences. This approach may be useful for validating non-canonical protein identification and discovering functionally relevant isoforms in the heart.


Asunto(s)
Empalme Alternativo , Biología Computacional , Miocardio/metabolismo , Isoformas de Proteínas , Proteoma , Proteómica , Biomarcadores , Biología Computacional/métodos , Humanos , Aprendizaje Automático , Péptidos , Proteómica/métodos , Espectrometría de Masas en Tándem
11.
Allergy ; 76(4): 1123-1135, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-32799375

RESUMEN

BACKGROUND: The receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) is implicated in COPD. Although these receptors share common ligands and signalling pathways, it is not known whether they act in concert to drive pathological processes in COPD. We examined the impact of RAGE and/or TLR4 gene deficiency in a mouse model of COPD and also determined whether expression of these receptors correlates with airway neutrophilia and airway hyperresponsiveness (AHR) in COPD patients. METHODS: We measured airway inflammation and AHR in wild-type, RAGE-/- , TLR4-/- and TLR4-/- RAGE-/- mice following acute exposure to cigarette smoke (CS). We also examined the impact of smoking status on AGER (encodes RAGE) and TLR4 bronchial gene expression in patients with and without COPD. Finally, we determined whether expression of these receptors correlates with airway neutrophilia and AHR in COPD patients. RESULTS: RAGE-/- mice were protected against CS-induced neutrophilia and AHR. In contrast, TLR4-/- mice were not protected against CS-induced neutrophilia and had more severe CS-induced AHR. TLR4-/- RAGE-/- mice were not protected against CS-induced neutrophilia but were partially protected against CS-induced mediator release and AHR. Current smoking was associated with significantly lower AGER and TLR4 expression irrespective of COPD status, possibly reflecting negative feedback regulation. However, consistent with preclinical findings, AGER expression correlated with higher sputum neutrophil counts and more severe AHR in COPD patients. TLR4 expression did not correlate with neutrophilic inflammation or AHR. CONCLUSIONS: Inhibition of RAGE but not TLR4 signalling may protect against airway neutrophilia and AHR in COPD.


Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica , Hipersensibilidad Respiratoria , Animales , Antígenos de Neoplasias , Humanos , Ratones , Proteínas Quinasas Activadas por Mitógenos , Enfermedad Pulmonar Obstructiva Crónica/genética , Receptor para Productos Finales de Glicación Avanzada/genética , Fumar , Receptor Toll-Like 4/genética
12.
Circ Res ; 125(7): 662-677, 2019 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-31409188

RESUMEN

RATIONALE: Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in preclinical models of heart failure (HF). However, since the inhibitors target BRD4 ubiquitously, it is unclear whether this chromatin reader protein functions in cell type-specific manner to control pathological myocardial fibrosis. Furthermore, the molecular mechanisms by which BRD4 stimulates the transcriptional program for cardiac fibrosis remain unknown. OBJECTIVE: We sought to test the hypothesis that BRD4 functions in a cell-autonomous and signal-responsive manner to control activation of cardiac fibroblasts, which are the major extracellular matrix-producing cells of the heart. METHODS AND RESULTS: RNA-sequencing, mass spectrometry, and cell-based assays employing primary adult rat ventricular fibroblasts demonstrated that BRD4 functions as an effector of TGF-ß (transforming growth factor-ß) signaling to stimulate conversion of quiescent cardiac fibroblasts into Periostin (Postn)-positive cells that express high levels of extracellular matrix. These findings were confirmed in vivo through whole-transcriptome analysis of cardiac fibroblasts from mice subjected to transverse aortic constriction and treated with the small molecule BRD4 inhibitor, JQ1. Chromatin immunoprecipitation-sequencing revealed that BRD4 undergoes stimulus-dependent, genome-wide redistribution in cardiac fibroblasts, becoming enriched on a subset of enhancers and super-enhancers, and leading to RNA polymerase II activation and expression of downstream target genes. Employing the Sertad4 (SERTA domain-containing protein 4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 MAPK (mitogen-activated protein kinase) and provide evidence of a critical function for Sertad4 in TGF-ß-mediated cardiac fibroblast activation. CONCLUSIONS: These findings define BRD4 as a central regulator of the pro-fibrotic cardiac fibroblast phenotype, establish a p38-dependent signaling circuit for epigenetic reprogramming in heart failure, and uncover a novel role for Sertad4. The work provides a mechanistic foundation for the development of BRD4 inhibitors as targeted anti-fibrotic therapies for the heart.


Asunto(s)
Cromatina/metabolismo , Insuficiencia Cardíaca/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Miofibroblastos/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Animales , Azepinas/farmacología , Azepinas/uso terapéutico , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Elementos de Facilitación Genéticos , Epigénesis Genética , Matriz Extracelular/metabolismo , Femenino , Fibrosis , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/genética , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Unión Proteica , ARN Polimerasa II/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Transcriptoma , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Triazoles/farmacología , Triazoles/uso terapéutico , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
13.
J Proteome Res ; 18(12): 4231-4239, 2019 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-31599600

RESUMEN

A steady increase in the incidence of osteoarthritis and other rheumatic diseases has been observed in recent decades, including autoimmune conditions such as rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis, and Sjögren's syndrome. Rheumatic and autoimmune diseases (RADs) are characterized by the inflammation of joints, muscles, or other connective tissues. In addition to often experiencing debilitating mobility and pain, RAD patients are also at a higher risk of suffering comorbidities such as cardiovascular or infectious events. Given the socioeconomic impact of RADs, broad research efforts have been dedicated to these diseases worldwide. In the present work, we applied literature mining platforms to identify "popular" proteins closely related to RADs. The platform is based on publicly available literature. The results not only will enable the systematic prioritization of candidates to perform targeted proteomics studies but also may lead to a greater insight into the key pathogenic processes of these disorders.


Asunto(s)
Enfermedades Autoinmunes/metabolismo , Proteínas/metabolismo , Proteoma , Enfermedades Reumáticas/metabolismo , Artritis Reumatoide/metabolismo , Minería de Datos , Humanos , Osteoartritis/metabolismo
14.
Mol Cell ; 44(2): 177-90, 2011 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-21856199

RESUMEN

Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (WT) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both WT and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.


Asunto(s)
Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , Proteínas Mitocondriales/metabolismo , Sirtuina 3/genética , Acetilación , Animales , Dieta Alta en Grasa , Humanos , Ratones , Ratones Noqueados , Modelos Biológicos , Sirtuina 3/metabolismo
15.
Adv Exp Med Biol ; 1124: 381-422, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31183836

RESUMEN

Airway smooth muscle (ASM) extends from the trachea throughout the bronchial tree to the terminal bronchioles. In utero, spontaneous phasic contraction of fetal ASM is critical for normal lung development by regulating intraluminal fluid movement, ASM differentiation, and release of key growth factors. In contrast, phasic contraction appears to be absent in the adult lung, and regulation of tonic contraction and airflow is under neuronal and humoral control. Accumulating evidence suggests that changes in ASM responsiveness contribute to the pathophysiology of lung diseases with lifelong health impacts.Functional assessments of fetal and adult ASM and airways have defined pharmacological responses and signaling pathways that drive airway contraction and relaxation. Studies using precision-cut lung slices, in which contraction of intrapulmonary airways and ASM calcium signaling can be assessed simultaneously in situ, have been particularly informative. These combined approaches have defined the relative importance of calcium entry into ASM and calcium release from intracellular stores as drivers of spontaneous phasic contraction in utero and excitation-contraction coupling.Increased contractility of ASM in asthma contributes to airway hyperresponsiveness. Studies using animal models and human ASM and airways have characterized inflammatory and other mechanisms underlying increased reactivity to contractile agonists and reduced bronchodilator efficacy of ß2-adrenoceptor agonists in severe diseases. Novel bronchodilators and the application of bronchial thermoplasty to ablate increased ASM within asthmatic airways have the potential to overcome limitations of current therapies. These approaches may directly limit excessive airway contraction to improve outcomes for difficult-to-control asthma and other chronic lung diseases.


Asunto(s)
Señalización del Calcio , Contracción Muscular , Músculo Liso/fisiología , Músculo Liso/fisiopatología , Fenómenos Fisiológicos Respiratorios , Animales , Asma/fisiopatología , Broncodilatadores , Humanos , Pulmón , Sistema Respiratorio/fisiopatología
16.
J Proteome Res ; 17(12): 4267-4278, 2018 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-30256117

RESUMEN

Identifying the genes and proteins associated with a biological process or disease is a central goal of the biomedical research enterprise. However, relatively few systematic approaches are available that provide objective evaluation of the genes or proteins known to be important to a research topic, and hence researchers often rely on subjective evaluation of domain experts and laborious manual literature review. Computational bibliometric analysis, in conjunction with text mining and data curation, attempts to automate this process and return prioritized proteins in any given research topic. We describe here a method to identify and rank protein-topic relationships by calculating the semantic similarity between a protein and a query term in the biomerical literature while adjusting for the impact and immediacy of associated research articles. We term the calculated metric the weighted copublication distance (WCD) and show that it compares well to related approaches in predicting benchmark protein lists in multiple biological processes. We used WCD to extract prioritized "popular proteins" across multiple cell types, subanatomical regions, and standardized vocabularies containing over 20 000 human disease terms. The collection of protein-disease associations across the resulting human "diseasome" supports data analytical workflows to perform reverse protein-to-disease queries and functional annotation of experimental protein lists. We envision that the described improvement to the popular proteins strategy will be useful for annotating protein lists and guiding method development efforts as well as generating new hypotheses on understudied disease proteins using bibliometric information.


Asunto(s)
Bibliometría , Enfermedad/etiología , Proteínas/fisiología , Semántica , Investigación Biomédica/métodos , Minería de Datos/métodos , Humanos , Anotación de Secuencia Molecular
18.
Am J Respir Cell Mol Biol ; 55(6): 858-868, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27482635

RESUMEN

Bronchopulmonary dysplasia (BPD) is a chronic disease of extreme prematurity that has serious long-term consequences including increased asthma risk. We earlier identified IL-1 receptor antagonist (IL-1Ra) as a potent inhibitor of murine BPD induced by combining perinatal inflammation (intraperitoneal LPS to pregnant dams) and exposure of pups to hyperoxia (fraction of inspired oxygen = 0.65). In this study, we determined whether airway remodeling and hyperresponsiveness similar to asthma are evident in this model, and whether IL-1Ra is protective. During 28-day exposure to air or hyperoxia, pups received vehicle or 10 mg/kg IL-1Ra by daily subcutaneous injection. Lungs were then prepared for histology and morphometry of alveoli and airways, or for real-time PCR, or inflated with agarose to prepare precision-cut lung slices to visualize ex vivo intrapulmonary airway contraction and relaxation by phase-contrast microscopy. In pups reared under normoxic conditions, IL-1Ra treatment did not affect alveolar or airway structure or airway responses. Pups reared in hyperoxia developed a severe BPD-like lung disease, with fewer, larger alveoli, increased subepithelial collagen, and increased expression of α-smooth muscle actin and cyclin D1. After hyperoxia, methacholine elicited contraction with similar potency but with an increased maximum reduction in lumen area (air, 44%; hyperoxia, 89%), whereas dilator responses to salbutamol were maintained. IL-1Ra treatment prevented hyperoxia-induced alveolar disruption and airway fibrosis but, surprisingly, not the increase in methacholine-induced airway contraction. The current study is the first to demonstrate ex vivo airway hyperreactivity caused by systemic maternal inflammation and postnatal hyperoxia, and it reveals further preclinical mechanistic insights into IL-1Ra as a treatment targeting key pathophysiological features of BPD.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Hiperreactividad Bronquial/complicaciones , Hiperreactividad Bronquial/metabolismo , Displasia Broncopulmonar/complicaciones , Displasia Broncopulmonar/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Albuterol/farmacología , Animales , Hiperreactividad Bronquial/patología , Hiperreactividad Bronquial/fisiopatología , Displasia Broncopulmonar/patología , Displasia Broncopulmonar/fisiopatología , Modelos Animales de Enfermedad , Femenino , Hiperoxia/complicaciones , Hiperoxia/metabolismo , Hiperoxia/patología , Hiperoxia/fisiopatología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Ratones Endogámicos C57BL , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Embarazo , Alveolos Pulmonares/patología
19.
J Proteome Res ; 15(11): 4126-4134, 2016 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-27356587

RESUMEN

Amidst the proteomes of human tissues lie subsets of proteins that are closely involved in conserved pathophysiological processes. Much of biomedical research concerns interrogating disease signature proteins and defining their roles in disease mechanisms. With advances in proteomics technologies, it is now feasible to develop targeted proteomics assays that can accurately quantify protein abundance as well as their post-translational modifications; however, with rapidly accumulating number of studies implicating proteins in diseases, current resources are insufficient to target every protein without judiciously prioritizing the proteins with high significance and impact for assay development. We describe here a data science method to prioritize and expedite assay development on high-impact proteins across research fields by leveraging the biomedical literature record to rank and normalize proteins that are popularly and preferentially published by biomedical researchers. We demonstrate this method by finding priority proteins across six major physiological systems (cardiovascular, cerebral, hepatic, renal, pulmonary, and intestinal). The described method is data-driven and builds upon the collective knowledge of previous publications referenced on PubMed to lend objectivity to target selection. The method and resulting popular protein lists may also be useful for exploring biological processes associated with various physiological systems and research topics, in addition to benefiting ongoing efforts to facilitate the broad translation of proteomics technologies.


Asunto(s)
Biología Computacional/métodos , Proteínas/análisis , Proteómica/métodos , Química Encefálica , Sistema Cardiovascular/química , Humanos , Intestinos/química , Riñón/química , Hígado/química , Pulmón/química
20.
Clin Proteomics ; 13: 23, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27980500

RESUMEN

Proteomics plays an increasingly important role in our quest to understand cardiovascular biology. Fueled by analytical and computational advances in the past decade, proteomics applications can now go beyond merely inventorying protein species, and address sophisticated questions on cardiac physiology. The advent of massive mass spectrometry datasets has in turn led to increasing intersection between proteomics and big data science. Here we review new frontiers in technological developments and their applications to cardiovascular medicine. The impact of big data science on cardiovascular proteomics investigations and translation to medicine is highlighted.

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