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1.
Circ Res ; 134(10): 1276-1291, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38623763

RESUMO

BACKGROUND: Hypertension is characterized by CD8+ (cluster differentiation 8) T cell activation and infiltration into peripheral tissues. CD8+ T cell activation requires proteasomal processing of antigenic proteins. It has become clear that isoLG (isolevuglandin)-adduced peptides are antigenic in hypertension; however, IsoLGs inhibit the constitutive proteasome. We hypothesized that immunoproteasomal processing of isoLG-adducts is essential for CD8+ T cell activation and inflammation in hypertension. METHODS: IsoLG adduct processing was studied in murine dendritic cells (DCs), endothelial cells (ECs), and B8 fibroblasts. The role of the proteasome and the immunoproteasome in Ang II (angiotensin II)-induced hypertension was studied in C57BL/6 mice treated with bortezomib or the immunoproteasome inhibitor PR-957 and by studying mice lacking 3 critical immunoproteasome subunits (triple knockout mouse). We also examined hypertension in mice lacking the critical immunoproteasome subunit LMP7 (large multifunctional peptidase 7) specifically in either DCs or ECs. RESULTS: We found that oxidant stress increases the presence of isoLG adducts within MHC-I (class I major histocompatibility complex), and immunoproteasome overexpression augments this. Pharmacological or genetic inhibition of the immunoproteasome attenuated hypertension and tissue inflammation. Conditional deletion of LMP7 in either DCs or ECs attenuated hypertension and vascular inflammation. Finally, we defined the role of the innate immune receptors STING (stimulator of interferon genes) and TLR7/8 (toll-like receptor 7/8) as drivers of LMP7 expression in ECs. CONCLUSIONS: These studies define a previously unknown role of the immunoproteasome in DCs and ECs in CD8+ T cell activation. The immunoproteasome in DCs and ECs is critical for isoLG-adduct presentation to CD8+ T cells, and in the endothelium, this guides homing and infiltration of T cells to specific tissues.


Assuntos
Bortezomib , Linfócitos T CD8-Positivos , Células Dendríticas , Hipertensão , Complexo de Endopeptidases do Proteassoma , Animais , Masculino , Camundongos , Angiotensina II , Bortezomib/farmacologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/imunologia , Fibroblastos/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Hipertensão/metabolismo , Hipertensão/imunologia , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oligopeptídeos , Estresse Oxidativo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia
2.
Circ Res ; 135(1): 138-154, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38662804

RESUMO

BACKGROUND: The biological mechanisms linking environmental exposures with cardiovascular disease pathobiology are incompletely understood. We sought to identify circulating proteomic signatures of environmental exposures and examine their associations with cardiometabolic and respiratory disease in observational cohort studies. METHODS: We tested the relations of >6500 circulating proteins with 29 environmental exposures across the built environment, green space, air pollution, temperature, and social vulnerability indicators in ≈3000 participants of the CARDIA study (Coronary Artery Risk Development in Young Adults) across 4 centers using penalized and ordinary linear regression. In >3500 participants from FHS (Framingham Heart Study) and JHS (Jackson Heart Study), we evaluated the prospective relations of proteomic signatures of the envirome with cardiovascular disease and mortality using Cox models. RESULTS: Proteomic signatures of the envirome identified novel/established cardiovascular disease-relevant pathways including DNA damage, fibrosis, inflammation, and mitochondrial function. The proteomic signatures of the envirome were broadly related to cardiometabolic disease and respiratory phenotypes (eg, body mass index, lipids, and left ventricular mass) in CARDIA, with replication in FHS/JHS. A proteomic signature of social vulnerability was associated with a composite of cardiovascular disease/mortality (1428 events; FHS: hazard ratio, 1.16 [95% CI, 1.08-1.24]; P=1.77×10-5; JHS: hazard ratio, 1.25 [95% CI, 1.14-1.38]; P=6.38×10-6; hazard ratio expressed as per 1 SD increase in proteomic signature), robust to adjustment for known clinical risk factors. CONCLUSIONS: Environmental exposures are related to an inflammatory-metabolic proteome, which identifies individuals with cardiometabolic disease and respiratory phenotypes and outcomes. Future work examining the dynamic impact of the environment on human cardiometabolic health is warranted.


Assuntos
Fatores de Risco Cardiometabólico , Doenças Cardiovasculares , Exposição Ambiental , Proteômica , Humanos , Proteômica/métodos , Feminino , Masculino , Exposição Ambiental/efeitos adversos , Adulto , Pessoa de Meia-Idade , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/epidemiologia , Estudos Prospectivos , Adulto Jovem
3.
Arterioscler Thromb Vasc Biol ; 44(4): 969-975, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38385288

RESUMO

BACKGROUND: Preeclampsia is a hypertensive disorder of pregnancy characterized by widespread vascular inflammation. It occurs frequently in pregnancy, often without known risk factors, and has high rates of maternal and fetal morbidity and mortality. Identification of biomarkers that predict preeclampsia and its cardiovascular sequelae before clinical onset, or even before pregnancy, is a critical unmet need for the prevention of adverse pregnancy outcomes. METHODS: We explored differences in cardiovascular proteomics (Olink Explore 384) in 256 diverse pregnant persons across 2 centers (26% Hispanic, 21% Black). RESULTS: We identified significant differences in plasma abundance of markers associated with angiogenesis, blood pressure, cell adhesion, inflammation, and metabolism between individuals delivering with preeclampsia and controls, some of which have not been widely described previously and are not represented in the preeclampsia placental transcriptome. While we observed a broadly similar pattern in early (<34 weeks) versus late (≥34 weeks) preeclampsia, several proteins related to hemodynamic stress, hemostasis, and immune response appeared to be more highly dysregulated in early preeclampsia relative to late preeclampsia. CONCLUSIONS: These results demonstrate the value of performing targeted proteomics using a panel of cardiovascular biomarkers to identify biomarkers relevant to preeclampsia pathophysiology and highlight the need for larger multiomic studies to define modifiable pathways of surveillance and intervention upstream to preeclampsia diagnosis.


Assuntos
Doenças Cardiovasculares , Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Placenta , Resultado da Gravidez , Biomarcadores , Inflamação/complicações , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/complicações , Fator de Crescimento Placentário
4.
Am J Physiol Lung Cell Mol Physiol ; 327(4): L473-L486, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39010826

RESUMO

Cystic fibrosis-related diabetes (CFRD), the most common comorbidity in cystic fibrosis (CF), leads to increased mortality by accelerating the decline in lung function. Scnn1b-Tg transgenic mice overexpressing the epithelial sodium channel ß subunit exhibit spontaneous CF-like lung disease, including airway mucus obstruction and chronic inflammation. Here, we established a chronic CFRD-like model using Scnn1b-Tg mice made diabetic by injection of streptozotocin (STZ). In Ussing chamber recordings of the trachea, Scnn1b-Tg mice exhibited larger amiloride-sensitive currents and forskolin-activated currents, without a difference in adenosine triphosphate (ATP)-activated currents compared with wild-type (WT) littermates. Both diabetic WT (WT-D) and diabetic Scnn1b-Tg (Scnn1b-Tg-D) mice on the same genetic background exhibited substantially elevated blood glucose at 8 wk; glucose levels also were elevated in bronchoalveolar lavage fluid (BALF). Bulk lung RNA-seq data showed significant differences between WT-D and Scnn1b-Tg-D mice. Neutrophil counts in BALF were substantially increased in Scnn1b-Tg-D lungs compared with controls (Scnn1b-Tg-con) and compared with WT-D lungs. Lung histology data showed enhanced parenchymal destruction, alveolar wall thickening, and neutrophilic infiltration in Scnn1b-Tg-D mice compared with WT-D mice, consistent with the development of a spontaneous lung infection. We intranasally administered Pseudomonas aeruginosa to induce lung infection in these mice for 24 h, which led to severe lung leukocytic infiltration and an increase in pro-inflammatory cytokine levels in the BALF. In summary, we established a chronic CFRD-like lung mouse model using the Scnn1b-Tg mice. The model can be used for future studies toward understanding the mechanisms underlying the lung pathophysiology associated with CFRD and developing novel therapeutics.NEW & NOTEWORTHY We established a chronic CFRD-like mouse model using the Scnn1b-Tg transgenic mice overexpressing the epithelial sodium channel ß subunit made diabetic by injection of streptozotocin. The results underscore the urgent need to develop novel therapeutics for CF lung disease.


Assuntos
Diabetes Mellitus Experimental , Canais Epiteliais de Sódio , Hiperglicemia , Pulmão , Camundongos Transgênicos , Animais , Canais Epiteliais de Sódio/metabolismo , Canais Epiteliais de Sódio/genética , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Camundongos , Pulmão/patologia , Pulmão/metabolismo , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Fibrose Cística/patologia , Fibrose Cística/complicações , Fibrose Cística/genética , Líquido da Lavagem Broncoalveolar , Masculino , Neutrófilos/metabolismo
5.
Gastroenterology ; 165(3): 656-669.e8, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37271289

RESUMO

BACKGROUND & AIMS: The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5AHyp) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5AHyp in the gut epithelium in inflammation and carcinogenesis. METHODS: We used human colon tissue messenger RNA samples and publicly available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis. RESULTS: We found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS messenger RNA and DHPS protein and reduced levels of EIF5AHyp. Similarly, colonic organoids from colitis patients also show down-regulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis. CONCLUSIONS: Hypusination in intestinal epithelial cells has a key role in the prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have a therapeutic impact.


Assuntos
Colite , Espermidina , Humanos , Animais , Camundongos , Espermidina/farmacologia , Espermidina/metabolismo , Proteômica , Fatores de Iniciação de Peptídeos/genética , Fatores de Iniciação de Peptídeos/metabolismo , Carcinogênese/genética , Colite/induzido quimicamente , Colite/genética , Colite/prevenção & controle , Homeostase , Inflamação
6.
Brief Bioinform ; 23(2)2022 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-35048125

RESUMO

Normalization and batch correction are critical steps in processing single-cell RNA sequencing (scRNA-seq) data, which remove technical effects and systematic biases to unmask biological signals of interest. Although a number of computational methods have been developed, there is no guidance for choosing appropriate procedures in different scenarios. In this study, we assessed the performance of 28 scRNA-seq noise reduction procedures in 55 scenarios using simulated and real datasets. The scenarios accounted for multiple biological and technical factors that greatly affect the denoising performance, including relative magnitude of batch effects, the extent of cell population imbalance, the complexity of cell group structures, the proportion and the similarity of nonoverlapping cell populations, dropout rates and variable library sizes. We used multiple quantitative metrics and visualization of low-dimensional cell embeddings to evaluate the performance on batch mixing while preserving the original cell group and gene structures. Based on our results, we specified technical or biological factors affecting the performance of each method and recommended proper methods in different scenarios. In addition, we highlighted one challenging scenario where most methods failed and resulted in overcorrection. Our studies not only provided a comprehensive guideline for selecting suitable noise reduction procedures but also pointed out unsolved issues in the field, especially the urgent need of developing metrics for assessing batch correction on imperceptible cell-type mixing.


Assuntos
Análise de Célula Única , Software , Perfilação da Expressão Gênica/métodos , Biblioteca Gênica , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Sequenciamento do Exoma
7.
BMC Cancer ; 24(1): 441, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38594604

RESUMO

BACKGROUND: We recently found that epiplakin 1 (EPPK1) alterations were present in 12% of lung adenocarcinoma (LUAD) cases and were associated with a poor prognosis in early-stage LUAD when combined with other molecular alterations. This study aimed to identify a probable crucial role for EPPK1 in cancer development. METHODS: EPPK1 mRNA and protein expression was analyzed with clinical variables. Normal bronchial epithelial cell lines were exposed to cigarette smoke for 16 weeks to determine whether EPPK1 protein expression was altered after exposure. Further, we used CRISPR-Cas9 to knock out (KO) EPPK1 in LUAD cell lines and observed how the cancer cells were altered functionally and genetically. RESULTS: EPPK1 protein expression was associated with smoking and poor prognosis in early-stage LUAD. Moreover, a consequential mesenchymal-to-epithelial transition was observed, subsequently resulting in diminished cell proliferation and invasion after EPPK1 KO. RNA sequencing revealed that EPPK1 KO induced downregulation of 11 oncogenes, 75 anti-apoptosis, and 22 angiogenesis genes while upregulating 8 tumor suppressors and 12 anti-cell growth genes. We also observed the downregulation of MYC and upregulation of p53 expression at both protein and RNA levels following EPPK1 KO. Gene ontology enrichment analysis of molecular functions highlighted the correlation of EPPK1 with the regulation of mesenchymal cell proliferation, mesenchymal differentiation, angiogenesis, and cell growth after EPPK1 KO. CONCLUSIONS: Our data suggest that EPPK1 is linked to smoking, epithelial to mesenchymal transition, and the regulation of cancer progression, indicating its potential as a therapeutic target for LUAD.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Transição Epitelial-Mesenquimal/genética , Prognóstico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma/patologia , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral
8.
Amino Acids ; 56(1): 63, 2024 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-39427081

RESUMO

Cystathionine γ-lyase (CTH) is a critical enzyme in the reverse transsulfuration pathway, the major route for the metabolism of sulfur-containing amino acids, notably converting cystathionine to cysteine. We reported that CTH supports gastritis induced by the pathogen Helicobacter pylori. Herein our aim was to investigate the role of CTH in colonic inflammation. First, we found that CTH is induced in the colon mucosa in mice with dextran sulfate sodium-induced colitis. Expression of CTH was completely absent in the colon of Cth-/- mice. We observed that clinical and histological parameters are ameliorated in Cth-deficient mice compared to wild-type animals. However, Cth deletion had no effect on tumorigenesis and the level of dysplasia in mice treated with azoxymethane-DSS, as a reliable model of colitis-associated carcinogenesis. Mechanistically, we determined that the deletion of the gene Slc7a11 encoding for solute carrier family 7 member 11, the transporter of the anionic form of cysteine, does not affect DSS colitis. Lastly, we found that the richness and diversity of the fecal microbiota were significantly increased in Cth-/- mice compared to both WT and Slc7a11-/- mice. In conclusion, our data suggest that the enzyme CTH represents a target for clinical intervention in patients with inflammatory bowel disease, potentially by beneficially reshaping the composition of the gut microbiota.


Assuntos
Colite , Colo , Cistationina gama-Liase , Sulfato de Dextrana , Microbioma Gastrointestinal , Camundongos Knockout , Animais , Camundongos , Colite/induzido quimicamente , Colite/metabolismo , Colite/microbiologia , Colite/patologia , Cistationina gama-Liase/metabolismo , Cistationina gama-Liase/genética , Colo/microbiologia , Colo/metabolismo , Colo/patologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
9.
Am J Respir Crit Care Med ; 207(10): 1345-1357, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-36622818

RESUMO

Rationale and Objectives: Up to 20% of idiopathic interstitial lung disease is familial, referred to as familial pulmonary fibrosis (FPF). An integrated analysis of FPF genetic risk was performed by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds. Methods: Whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds was performed, followed by cosegregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell-type enrichment analysis, and coexpression network construction. Measurements and Main Results: It was found that 14.9-23.4% of genetic risk in kindreds could be explained by RVs in genes previously linked to FPF, predominantly telomere-related genes. New candidate genes were identified in a small number of families-including SYDE1, SERPINB8, GPR87, and NETO1-and tools were developed for evaluation and prioritization of RV-containing genes across kindreds. Several pathways were enriched for RV-containing genes in FPF, including focal adhesion and mitochondrial complex I assembly. By combining single-cell transcriptomics with prioritized candidate genes, expression of RV-containing genes was discovered to be enriched in smooth muscle cells, type II alveolar epithelial cells, and endothelial cells. Conclusions: In the most comprehensive FPF genetic study to date, the prevalence of RVs in known FPF-related genes was defined, and new candidate genes and pathways relevant to FPF were identified. However, new RV-containing genes shared across multiple kindreds were not identified, thereby suggesting that heterogeneous genetic variants involving a variety of genes and pathways mediate genetic risk in most FPF kindreds.


Assuntos
Doenças Pulmonares Intersticiais , Fibrose Pulmonar , Humanos , Fibrose Pulmonar/genética , Células Endoteliais , Doenças Pulmonares Intersticiais/genética , Fatores de Risco , Telômero , Predisposição Genética para Doença/genética , Receptores de Ácidos Lisofosfatídicos/genética
10.
Can J Urol ; 31(2): 11840-11846, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38642462

RESUMO

INTRODUCTION: There are multiple historic reports linking lower urinary tract symptoms (LUTS) in children with food allergies (FA), but contemporary studies are sparse. The objective of this study was to evaluate a potential link between FA and LUTS in the pediatric population. We hypothesized that children with FAs are more likely to have LUTS. MATERIALS AND METHODS: After local IRB approval, pediatric patients (6-17 years [y]) with FAs proven by positive skin prick and/or serum IgE testing were invited to participate. A control group of pediatric patients without FAs was also recruited. All families/legal guardians signed informed consent, and all children signed written assent. Each participant filled out the Vancouver Symptom Score (VSS), a validated questionnaire for dysfunctional elimination syndrome, and the Pediatric Incontinence Questionnaire (PinQ), a validated quality of life assessment for children with bladder dysfunction. Demographic and clinical information were obtained retrospectively. RESULTS: From 2019-2020, 26 children with FAs and 57 without agreed to participate. Mean age was 9.3 y (IQR 7.9 y-13.5 y). There were no differences in gender, age, or race between the two cohorts. There were no significant differences between the two groups in mean VSS score or mean PinQ score. Four children with FAs (15%) and 15 children without (26%) had VSS score ≥ 11 (p = 0.339), indicating dysfunctional elimination. The median PinQ score was 0 (IQR 0-2) in both cohorts. CONCLUSIONS: This study did not identify an association between FAs and LUTS in a population of pediatric patients with laboratory proven FAs.


Assuntos
Hipersensibilidade Alimentar , Sintomas do Trato Urinário Inferior , Incontinência Urinária , Humanos , Criança , Estudos de Casos e Controles , Qualidade de Vida , Estudos Retrospectivos , Sintomas do Trato Urinário Inferior/diagnóstico , Incontinência Urinária/complicações , Inquéritos e Questionários , Hipersensibilidade Alimentar/complicações
11.
Gastroenterology ; 162(3): 813-827.e8, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34767785

RESUMO

BACKGROUND & AIMS: Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine oxidase (SMOX), which generates spermidine (Spd), regulates colitis. Here we determined whether Spd treatment reduces colitis and carcinogenesis. METHODS: SMOX was quantified in human colitis and associated dysplasia using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. We used wild-type (WT) and Smox-/- C57BL/6 mice treated with dextran sulfate sodium (DSS) or azoxymethane (AOM)-DSS as models of colitis and CAC, respectively. Mice with epithelial-specific deletion of Apc were used as a model of sporadic colon cancer. Animals were supplemented or not with Spd in the drinking water. Colonic polyamines, inflammation, tumorigenesis, transcriptomes, and microbiomes were assessed. RESULTS: SMOX messenger RNA levels were decreased in human ulcerative colitis tissues and inversely correlated with disease activity, and SMOX protein was reduced in colitis-associated dysplasia. DSS colitis and AOM-DSS-induced dysplasia and tumorigenesis were worsened in Smox-/- vs WT mice and improved in both genotypes with Spd. Tumor development caused by Apc deletion was also reduced by Spd. Smox deletion and AOM-DSS treatment were both strongly associated with increased expression of α-defensins, which was reduced by Spd. A shift in the microbiome, with reduced abundance of Prevotella and increased Proteobacteria and Deferribacteres, occurred in Smox-/- mice and was reversed with Spd. CONCLUSIONS: Loss of SMOX is associated with exacerbated colitis and CAC, increased α-defensin expression, and dysbiosis of the microbiome. Spd supplementation reverses these phenotypes, indicating that it has potential as an adjunctive treatment for colitis and chemopreventive for colon carcinogenesis.


Assuntos
Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Colite/genética , Neoplasias do Colo/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Espermidina/uso terapêutico , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Azoximetano , Colite/induzido quimicamente , Colite/enzimologia , Colite/prevenção & controle , Colite Ulcerativa/enzimologia , Colite Ulcerativa/genética , Colo/enzimologia , Colo/patologia , Neoplasias do Colo/prevenção & controle , Sulfato de Dextrana , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mucosa Intestinal/enzimologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Lesões Pré-Cancerosas/enzimologia , Fatores de Proteção , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Espermidina/metabolismo , Espermidina/farmacologia , Redução de Peso/efeitos dos fármacos , alfa-Defensinas/genética , alfa-Defensinas/metabolismo , Poliamina Oxidase
13.
Neurourol Urodyn ; 42(6): 1431-1436, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37249147

RESUMO

PURPOSE: Surgical interventions in the urologic management of children with neurogenic bladder secondary to spina bifida aim to preserve upper tract function, prevent urinary tract infections, and optimize quality of life. However, since the introduction of intravesical onabotulinumtoxinA (Botox) in the management of these patients, the indications for choosing Botox over augmentation cystoplasty (AC) remain undefined. The objective of this study was to determine which factors lead patients to undergo Botox versus AC as a primary surgical treatment after failing medical management. METHODS: We retrospectively reviewed the records of pediatric patients with myelomeningocele undergoing either primary Botox or primary AC at our institution between 2013 and 2018. We recorded demographic and clinical information. We identified 10 important clinical decision-making factors: bladder trabeculation, vesicoureteral reflux, or hydronephrosis on imaging; end-filling pressure (EFP) ≥40 cm H2O, detrusor overactivity, detrusor-sphincter dyssynergia, or reduced capacity on urodynamic studies; physician-perceived bladder hostility; and patient/family desire for continence and independence. The presence of these factors was compared between patients undergoing either primary Botox or primary AC. RESULTS: We identified 14 and 50 myelomeningocele patients who underwent primary AC and primary Botox, respectively. We found no significant differences in age, sex, race, or history of reconstructive surgery (antegrade continence enema or catheterizable channel). For the 10 decision-making factors, desire for independence/continence (p = <0.001) and reduced capacity (p = 0.002) were significantly associated with AC, while trabeculation (p = 0.006), EFP ≥40 cm H2O (p = 0.029), rising slope (p = 0.019), and physician-perceived hostility (p = 0.012) were significantly more common with Botox. CONCLUSIONS: At our institution, quality of life measures prompted AC over objective urodynamic or imaging findings before attempting Botox. These findings support a shared decision-making approach when considering surgical intervention for neurogenic bladder secondary to myelomeningocele.


Assuntos
Toxinas Botulínicas Tipo A , Meningomielocele , Disrafismo Espinal , Bexiga Urinaria Neurogênica , Humanos , Criança , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinaria Neurogênica/etiologia , Bexiga Urinaria Neurogênica/cirurgia , Toxinas Botulínicas Tipo A/uso terapêutico , Meningomielocele/complicações , Meningomielocele/cirurgia , Estudos Retrospectivos , Qualidade de Vida , Disrafismo Espinal/complicações , Urodinâmica
14.
Cell Mol Life Sci ; 80(1): 9, 2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36495344

RESUMO

Gut microbes are associated with the development of depression based on extensive evidence. However, previous studies have led to conflicting reports on this association, posing challenges to the application of gut bacteria in the diagnostics and treatment of depression. To minimise heterogenicity in data analysis, the present meta-analysis adopted a standardised bioinformatics and statistical pipeline to analyse 16S rRNA sequences of 1827 samples from eight different cohorts. Although changes in the overall bacterial community were identified by our meta-analysis, depressive-correlated changes in alpha-diversity were absent. Enrichment of Bacteroidetes, Parabacteroides, Barnesiella, Bacteroides, and Bacteroides vulgatus, along with depletion in Firmicutes, Dialister, Oscillospiraceae UCG 003 and UCG 002, and Bacteroides plebeius, were observed in depressive-associated bacteria. By contrast, elevated L-glutamine degradation, and reduced L-glutamate and L-isoleucine biosynthesis were identified in depressive-associated microbiomes. After systemically reviewing the data of these collected cohorts, we have established a bacterial classifier to identify depressive symptoms with AUC 0.834 and 0.685 in the training and external validation dataset, respectively. Moreover, a low-risk bacterial cluster for depressive symptoms was identified, which was represented by a lower abundance of Escherichia-Shigella, and a higher abundance of Faecalibacterium, Oscillospiraceae UCG 002, Ruminococcus, and Christensenellaceae R.7 group.


Assuntos
Bactérias , Bacteroidetes , Humanos , RNA Ribossômico 16S/genética , Fezes/microbiologia , DNA Bacteriano , Bactérias/genética , Biomarcadores , Estudos de Coortes
15.
Gut ; 71(6): 1106-1116, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35140064

RESUMO

OBJECTIVE: The gut microbiota plays a key role in modulating host immune response. We conducted a prospective, observational study to examine gut microbiota composition in association with immune responses and adverse events in adults who have received the inactivated vaccine (CoronaVac; Sinovac) or the mRNA vaccine (BNT162b2; BioNTech; Comirnaty). DESIGN: We performed shotgun metagenomic sequencing in stool samples of 138 COVID-19 vaccinees (37 CoronaVac and 101 BNT162b2 vaccinees) collected at baseline and 1 month after second dose of vaccination. Immune markers were measured by SARS-CoV-2 surrogate virus neutralisation test and spike receptor-binding domain IgG ELISA. RESULTS: We found a significantly lower immune response in recipients of CoronaVac than BNT162b2 vaccines (p<0.05). Bifidobacterium adolescentis was persistently higher in subjects with high neutralising antibodies to CoronaVac vaccine (p=0.023) and their baseline gut microbiome was enriched in pathways related to carbohydrate metabolism (linear discriminant analysis (LDA) scores >2 and p<0.05). Neutralising antibodies in BNT162b2 vaccinees showed a positive correlation with the total abundance of bacteria with flagella and fimbriae including Roseburia faecis (p=0.028). The abundance of Prevotella copri and two Megamonas species were enriched in individuals with fewer adverse events following either of the vaccines indicating that these bacteria may play an anti-inflammatory role in host immune response (LDA scores>3 and p<0.05). CONCLUSION: Our study has identified specific gut microbiota markers in association with improved immune response and reduced adverse events following COVID-19 vaccines. Microbiota-targeted interventions have the potential to complement effectiveness of COVID-19 vaccines.


Assuntos
COVID-19 , Microbioma Gastrointestinal , Adulto , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Humanos , Imunogenicidade da Vacina , Estudos Prospectivos , SARS-CoV-2 , Vacinas Sintéticas , Vacinas de mRNA
16.
Gastroenterology ; 160(4): 1256-1268.e9, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33189701

RESUMO

BACKGROUND & AIMS: Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis. METHODS: The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils as models of H pylori-induced carcinogenesis and in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H pylori-infected INS-GAS mice was assessed by whole-exome sequencing. RESULTS: We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and intestinal metaplasia and in human gastric organoids infected with H pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity. CONCLUSIONS: Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations and are thus key targets for cancer chemoprevention.


Assuntos
Transformação Celular Neoplásica/imunologia , Neoplasias Associadas a Colite/imunologia , Lipídeos/imunologia , Lesões Pré-Cancerosas/imunologia , Neoplasias Gástricas/imunologia , Animais , Benzilaminas/farmacologia , Benzilaminas/uso terapêutico , Núcleo Celular/metabolismo , Transformação Celular Neoplásica/efeitos dos fármacos , Neoplasias Associadas a Colite/microbiologia , Neoplasias Associadas a Colite/patologia , Neoplasias Associadas a Colite/prevenção & controle , Modelos Animais de Doenças , Células Epiteliais , Mucosa Gástrica/citologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/imunologia , Mucosa Gástrica/patologia , Gastrite/imunologia , Gastrite/microbiologia , Gastrite/patologia , Gerbillinae , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/imunologia , Helicobacter pylori/isolamento & purificação , Humanos , Lipídeos/antagonistas & inibidores , Metaplasia/imunologia , Metaplasia/microbiologia , Metaplasia/patologia , Camundongos , Camundongos Transgênicos , Organoides , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/microbiologia , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/prevenção & controle
17.
Am J Physiol Heart Circ Physiol ; 323(5): H917-H933, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36083796

RESUMO

We have shown that excessive endothelial cell stretch causes release of growth arrest-specific 6 (GAS6), which activates the tyrosine kinase receptor Axl on monocytes and promotes immune activation and inflammation. We hypothesized that GAS6/Axl blockade would reduce renal and vascular inflammation and lessen renal dysfunction in the setting of chronic aortic remodeling. We characterized a model of aortic remodeling in mice following a 2-wk infusion of angiotensin II (ANG II). These mice had chronically increased pulse wave velocity, and their aortas demonstrated increased mural collagen. Mechanical testing revealed a marked loss of Windkessel function that persisted for 6 mo following ANG II infusion. Renal function studies showed a reduced ability to excrete a volume load, a progressive increase in albuminuria, and tubular damage as estimated by periodic acid Schiff staining. Treatment with the Axl inhibitor R428 beginning 2 mo after ANG II infusion had a minimal effect on aortic remodeling 2 mo later but reduced the infiltration of T cells, γ/δ T cells, and macrophages into the aorta and kidney and improved renal excretory capacity, reduced albuminuria, and reduced evidence of renal tubular damage. In humans, circulating Axl+/Siglec6+ dendritic cells and phospho-Axl+ cells correlated with pulse wave velocity and aortic compliance measured by transesophageal echo, confirming chronic activation of the GAS6/Axl pathway. We conclude that brief episodes of hypertension induce chronic aortic remodeling, which is associated with persistent low-grade inflammation of the aorta and kidneys and evidence of renal dysfunction. These events are mediated at least in part by GAS6/Axl signaling and are improved with Axl blockade.NEW & NOTEWORTHY In this study, a brief, 2-wk period of hypertension in mice led to progressive aortic remodeling, an increase in pulse wave velocity, and evidence of renal injury, dysfunction, and albuminuria. This end-organ damage was associated with persistent renal and aortic infiltration of CD8+ and γ/δ T cells. We show that this inflammatory response is likely due to GAS6/Axl signaling and can be ameliorated by blocking this pathway. We propose that the altered microvascular mechanical forces caused by increased pulse wave velocity enhance GAS6 release from the endothelium, which in turn activates Axl on myeloid cells, promoting the end-organ damage associated with aortic stiffening.


Assuntos
Hipertensão , Nefropatias , Animais , Humanos , Camundongos , Albuminúria/prevenção & controle , Angiotensina II/farmacologia , Aorta/metabolismo , Colágeno , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Ácido Periódico , Proteínas Proto-Oncogênicas/metabolismo , Análise de Onda de Pulso , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Tirosina Quinase Axl
18.
PLoS Comput Biol ; 16(6): e1007968, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32511223

RESUMO

Very short tandem repeats bear substantial genetic, evolutional, and pathological significance in genome analyses. Here, we compiled a census of tandem mono-nucleotide/di-nucleotide/tri-nucleotide repeats (MNRs/DNRs/TNRs) in GRCh38, which we term "polytracts" in general. Of the human genome, 144.4 million nucleotides (4.7%) are occupied by polytracts, and 0.47 million single nucleotides are identified as polytract hinges, i.e., break-points of tandem polytracts. Preliminary exploration of the census suggested polytract hinge sites and boundaries of AAC polytracts may bear a higher mapping error rate than other polytract regions. Further, we revealed landscapes of polytract enrichment with respect to nearly a hundred genomic features. We found MNRs, DNRs, and TNRs displayed noticeable difference in terms of locational enrichment for miscellaneous genomic features, especially RNA editing events. Non-canonical and C-to-U RNA-editing events are enriched inside and/or adjacent to MNRs, while all categories of RNA-editing events are under-represented in DNRs. A-to-I RNA-editing events are generally under-represented in polytracts. The selective enrichment of non-canonical RNA-editing events within MNR adjacency provides a negative evidence against their authenticity. To enable similar locational enrichment analyses in relation to polytracts, we developed a software Polytrap which can handle 11 reference genomes. Additionally, we compiled polytracts of four model organisms into a Track Hub which can be integrated into USCS Genome Browser as an official track for convenient visualization of polytracts.


Assuntos
DNA/genética , Genoma Humano , Repetições de Microssatélites/genética , RNA/genética , Humanos , Edição de RNA , Software
19.
Ann Behav Med ; 55(10): 956-969, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-33761527

RESUMO

BACKGROUND: Family members' responses to adults' diabetes and efforts to manage it vary widely. Multiple aspects of diabetes-specific family functioning have been identified as important for self-management and psychosocial well-being in theoretical (i.e., theories of social support and collaborative coping) and observational literature. PURPOSE: Develop a typological framework of diabetes-specific family functioning and examine cross-sectional associations between type and diabetes outcomes. METHODS: We used electronic health record (EHR) data to identify a cohort of 5,545 adults receiving outpatient care for type 2 diabetes and invited them to complete a survey assessing 10 dimensions of diabetes-specific family functioning. We used k-means cluster analysis to identify types. After type assignment, we used EHR data for the full cohort to generate sampling weights to correct for imbalance between participants and non-participants. We used weighted data to examine unadjusted associations between participant characteristics and type, and in regression models to examine associations between type and diabetes outcomes. Regression models were adjusted for sociodemographics, diabetes duration, and insulin status. RESULTS: We identified and named four types: Collaborative and Helpful (33.8%), Satisfied with Low Involvement (22.2%), Want More Involvement (29.6%), and Critically Involved (14.5%; reflecting the highest levels of criticism and harmful involvement). Across these types, hemoglobin A1c, diabetes distress, depressive symptoms, diabetes medication adherence, and diabetes self-efficacy worsened. After covariate adjustment, type remained independently associated with each diabetes outcome (all p's < .05). CONCLUSIONS: The typology extends theories of family support in diabetes and applications of the typology may lead to breakthroughs in intervention design, tailoring, and evaluation.


Assuntos
Diabetes Mellitus Tipo 2 , Autogestão , Adaptação Psicológica , Adulto , Estudos Transversais , Diabetes Mellitus Tipo 2/terapia , Hemoglobinas Glicadas/análise , Humanos , Apoio Social
20.
Am J Respir Crit Care Med ; 201(6): 697-706, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31747302

RESUMO

Rationale: We have a limited understanding of the molecular underpinnings of early adenocarcinoma (ADC) progression. We hypothesized that the behavior of early ADC can be predicted based on genomic determinants.Objectives: To identify genomic alterations associated with resected indolent and aggressive early lung ADCs.Methods: DNA was extracted from 21 ADCs in situ (AISs), 27 minimally invasive ADCs (MIAs), and 54 fully invasive ADCs. This DNA was subjected to deep next-generation sequencing and tested against a custom panel of 347 cancer genes.Measurements and Main Results: Sequencing data was analyzed for associations among tumor mutation burden, frequency of mutations or copy number alterations, mutation signatures, intratumor heterogeneity, pathway alterations, histology, and overall survival. We found that deleterious mutation burden was significantly greater in invasive ADC, whereas more copy number loss was observed in AIS and MIA. Intratumor heterogeneity establishes early, as in AIS. Twenty-one significantly mutated genes were shared among the groups. Mutation signature profiling did not vary significantly, although the APOBEC signature was associated with ADC and poor survival. Subclonal KRAS mutations and a gene signature consisting of PIK3CG, ATM, EPPK1, EP300, or KMT2C mutations were also associated with poor survival. Mutations of KRAS, TP53, and NF1 were found to increase in frequency from AIS and MIA to ADC. A cancer progression model revealed selective early and late drivers.Conclusions: Our results reveal several genetic driver events, clonality, and mutational signatures associated with poor outcome in early lung ADC, with potential future implications for the detection and management of ADC.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/fisiopatologia , Biomarcadores Tumorais/genética , Detecção Precoce de Câncer/métodos , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/fisiopatologia , Adulto , Idoso , Estudos de Coortes , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
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