RESUMO
Chronic inflammation is often associated with the development of tissue fibrosis, but how mesenchymal cell responses dictate pathological fibrosis versus resolution and healing remains unclear. Defining stromal heterogeneity and identifying molecular circuits driving extracellular matrix deposition and remodeling stands to illuminate the relationship between inflammation, fibrosis, and healing. We performed single-cell RNA-sequencing of colon-derived stromal cells and identified distinct classes of fibroblasts with gene signatures that are differentially regulated by chronic inflammation, including IL-11-producing inflammatory fibroblasts. We further identify a transcriptional program associated with trans-differentiation of mucosa-associated fibroblasts and define a functional gene signature associated with matrix deposition and remodeling in the inflamed colon. Our analysis supports a critical role for the metalloprotease Adamdec1 at the interface between tissue remodeling and healing during colitis, demonstrating its requirement for colon epithelial integrity. These findings provide mechanistic insight into how inflammation perturbs stromal cell behaviors to drive fibroblastic responses controlling mucosal matrix remodeling and healing.
Assuntos
Proteínas ADAM/imunologia , Colite/imunologia , Matriz Extracelular/metabolismo , Fibroblastos/imunologia , Mucosa Intestinal/imunologia , Células-Tronco Mesenquimais/imunologia , Proteínas ADAM/deficiência , Proteínas ADAM/genética , Animais , Diferenciação Celular , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Colo/imunologia , Colo/patologia , Matriz Extracelular/imunologia , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica , Humanos , Inflamação , Interleucina-11/genética , Interleucina-11/imunologia , Mucosa Intestinal/patologia , Masculino , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Análise de Célula Única , Dodecilsulfato de Sódio/administração & dosagem , Transcrição Gênica , Transcriptoma , Cicatrização/genética , Cicatrização/imunologiaRESUMO
The clear role of autophagy in human inflammatory diseases such as Crohn disease was first identified by genome-wide association studies and subsequently dissected in multiple mechanistic studies. ATG16L1 has been particularly well studied in knockout and hypomorph settings as well as models recapitulating the Crohn disease-associated T300A polymorphism. Interestingly, ATG16L1 has a single homolog, ATG16L2, which is independently implicated in diseases, including Crohn disease and systemic lupus erythematosus. However, the contribution of ATG16L2 to canonical autophagy pathways and other cellular functions is poorly understood. To better understand its role, we generated and analyzed the first, to our knowledge, ATG16L2 knockout mouse. Our results show that ATG16L1 and ATG16L2 contribute very distinctly to autophagy and cellular ontogeny in myeloid, lymphoid, and epithelial lineages. Dysregulation of any of these lineages could contribute to complex diseases like Crohn disease and systemic lupus erythematosus, highlighting the value of examining cell-specific effects. We also identify a novel genetic interaction between ATG16L2 and epithelial ATG16L1. These findings are discussed in the context of how these genes may contribute distinctly to human disease.
Assuntos
Morte Celular Autofágica , Proteínas Relacionadas à Autofagia , Proteínas de Transporte , Doença de Crohn , Lúpus Eritematoso Sistêmico , Animais , Morte Celular Autofágica/genética , Morte Celular Autofágica/imunologia , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/imunologia , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Modelos Animais de Doenças , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Knockout , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologiaRESUMO
BACKGROUND: Self-care interventions offer a solution to support the achievement of three goals of the World Health Organization (WHO): to improve universal health coverage, reach people in humanitarian situations, and improve health and well-being. In light of implementing WHO consolidated guidelines on self-care interventions to strengthen sexual and reproductive health (SRH) in the Eastern Mediterranean Region (EMR), especially during the COVID-19 pandemic, pharmacists from four different EMR countries discussed the current SRH situation, inequality gaps, barriers to SRH service access and the pharmacist's crucial role as a first-line responder to patients before, during and after COVID-19. CASE PRESENTATION: Self-care interventions for SRH allow health care providers to serve a greater number of patients, improve progress toward universal health coverage, and reach people in humanitarian crises. In fact, these interventions can be significantly enhanced by utilizing community pharmacists as first-line health care providers. This review highlights the important role of community pharmacists in promoting self-care interventions and empowering individuals, families and communities. As a result, well-informed individuals will be authoritative in their health decisions. Exploring self-care interventions in the EMR was done through reviewing selected SRH services delivery through community pharmacists before and during the COVID-19 pandemic in Egypt, Jordan, Lebanon and Somalia. Before the COVID-19 pandemic, community pharmacists were found to be excluded from both governmental and nongovernmental SRH programmes. During the pandemic, community pharmacists managed to support patients with self-care interventions, whether voluntarily or through their pharmacy associations. This highlights the need for the health care decision-makers to involve and support community pharmacists in influencing policies and promoting self-care interventions. CONCLUSION: Self-care interventions can increase individuals' choice and autonomy over SRH. Supporting community pharmacists will definitely strengthen SRH in the EMR and may help make the health system more efficient and more targeted.
Assuntos
COVID-19 , Acessibilidade aos Serviços de Saúde , Pandemias , Farmacêuticos , Saúde Reprodutiva , Autocuidado , Saúde Sexual , Tomada de Decisões , Difusão de Inovações , Egito , Feminino , Serviços de Saúde , Humanos , Jordânia , Líbano , Masculino , Região do Mediterrâneo , Papel Profissional , Serviços de Saúde Reprodutiva , SomáliaRESUMO
PURPOSE: This project examines ChatGPT's potential to enhance the readability of patient educational materials about interventional radiology (IR) procedures. METHODS AND MATERIALS: The descriptions of IR procedures from the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) were used as the original text. Readability scores were calculated using three metrics: Flesch Reading Ease (FRE), Gunning Fog (GF), and the Automated Readability Index (ARI) using an online calculator ( https://readabilityformulas.com ). FRE is scored on a scale of 0-100, where 100 indicates easy-to-read texts, and GF and ARI represent the grade level required to comprehend the text. The DISCERN instrument measured credibility and reliability. ChatGPT was prompted to simplify the texts to a fifth-grade reading level, with subsequent recalculation of readability and DISCERN scores for comparison. Statistical significance was determined using a Wilcoxon Signed-Rank Test. Articles were subsequently organized by subgroups and analyzed. RESULTS: 73 interventional radiology procedures from CIRSE were analyzed. The original FRE score was 47.2 (Difficult), improved to 78.4 (Fairly Easy) by ChatGPT. GF and ARI scores dropped from 14.4 and 11.2 to 7.8 and 5.8, respectively, after simplification, showing significant improvement (p < 0.001). However, the average DISCERN score decreased from 3.73 to 2.99 (p < 0.001) post-ChatGPT simplification. CONCLUSION: This study shows ChatGPT's ability to make interventional radiology descriptions more readable but highlights its struggle to maintain the original's reliability, suggesting the need for human review and prompt engineering to enhance outcomes. LEVEL OF EVIDENCE: Level 6.
Assuntos
Compreensão , Radiologia Intervencionista , Humanos , Educação de Pacientes como Assunto/métodos , Radiografia Intervencionista , Reprodutibilidade dos Testes , Letramento em SaúdeRESUMO
Tissue homeostasis is perturbed in a diversity of inflammatory pathologies. These changes can elicit endoplasmic reticulum (ER) stress, protein misfolding, and cell death. ER stress triggers the unfolded protein response (UPR), which can promote recovery of ER proteostasis and cell survival or trigger programmed cell death. Here, we leveraged single-cell RNA sequencing to define dynamic transcriptional states associated with the adaptive versus terminal UPR in the mouse intestinal epithelium. We integrated these transcriptional programs with genome-scale CRISPR screening to dissect the UPR pathway functionally. We identified QRICH1 as a key effector of the PERK-eIF2α axis of the UPR. QRICH1 controlled a transcriptional program associated with translation and secretory networks that were specifically up-regulated in inflammatory pathologies. Thus, QRICH1 dictates cell fate in response to pathological ER stress.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Estresse do Retículo Endoplasmático/genética , Regulação da Expressão Gênica , Inflamação/metabolismo , Proteostase/genética , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas/genética , Animais , Apoptose , Células Cultivadas , Proteínas de Ligação a DNA/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Humanos , Inflamação/genética , Inflamação/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Organoides , RNA-Seq , Análise de Célula Única , Fatores de Transcrição/genética , Transcrição Gênica , eIF-2 Quinase/metabolismoRESUMO
Host factors in the intestine help select for bacteria that promote health. Certain commensals can utilize mucins as an energy source, thus promoting their colonization. However, health conditions such as inflammatory bowel disease (IBD) are associated with a reduced mucus layer, potentially leading to dysbiosis associated with this disease. We characterize the capability of commensal species to cleave and transport mucin-associated monosaccharides and identify several Clostridiales members that utilize intestinal mucins. One such mucin utilizer, Peptostreptococcus russellii, reduces susceptibility to epithelial injury in mice. Several Peptostreptococcus species contain a gene cluster enabling production of the tryptophan metabolite indoleacrylic acid (IA), which promotes intestinal epithelial barrier function and mitigates inflammatory responses. Furthermore, metagenomic analysis of human stool samples reveals that the genetic capability of microbes to utilize mucins and metabolize tryptophan is diminished in IBD patients. Our data suggest that stimulating IA production could promote anti-inflammatory responses and have therapeutic benefits.