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1.
Pharmacol Ther ; 253: 108578, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38103794

RESUMEN

The treatment of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), remains challenging as current available antifibrotic agents are not effective in halting disease progression. Connective tissue growth factor (CTGF), also known as cellular communication factor 2 (CCN2), is a member of the CCN family of proteins that regulates cell signaling through cell surface receptors such as integrins, the activity of cytokines/growth factors, and the turnover of extracellular matrix (ECM) proteins. Accumulating evidence indicates that CTGF plays a crucial role in promoting lung fibrosis through multiple processes, including inducing transdifferentiation of fibroblasts to myofibroblasts, epithelial-mesenchymal transition (EMT), and cooperating with other fibrotic mediators such as TGF-ß. Increased expression of CTGF has been observed in fibrotic lungs and inhibiting CTGF signaling has been shown to suppress lung fibrosis in several animal models. Thus, the CTGF signaling pathway is emerging as a potential therapeutic target in IPF and other pulmonary fibrotic conditions. This review provides a comprehensive overview of the current evidence on the pathogenic role of CTGF in pulmonary fibrosis and discusses the current therapeutic agents targeting CTGF using a systematic review approach.


Asunto(s)
Factor de Crecimiento del Tejido Conjuntivo , Fibrosis Pulmonar Idiopática , Animales , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Fibrosis , Fibroblastos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/patología , Factor de Crecimiento Transformador beta1 , Pulmón/metabolismo
2.
Immunol Cell Biol ; 101(5): 412-427, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36862017

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. The accumulation of macrophages is associated with disease pathogenesis. The unfolded protein response (UPR) has been linked to macrophage activation in pulmonary fibrosis. To date, the impact of activating transcription factor 6 alpha (ATF6α), one of the UPR mediators, on the composition and function of pulmonary macrophage subpopulations during lung injury and fibrogenesis is not fully understood. We began by examining the expression of Atf6α in IPF patients' lung single-cell RNA sequencing dataset, archived surgical lung specimens, and CD14+ circulating monocytes. To assess the impact of ATF6α on pulmonary macrophage composition and pro-fibrotic function during tissue remodeling, we conducted an in vivo myeloid-specific deletion of Atf6α. Flow cytometric assessments of pulmonary macrophages were carried out in C57BL/6 and myeloid specific ATF6α-deficient mice in the context of bleomycin-induced lung injury. Our results demonstrated that Atf6α mRNA was expressed in pro-fibrotic macrophages found in the lung of a patient with IPF and in CD14+ circulating monocytes obtained from blood of a patient with IPF. After bleomycin administration, the myeloid-specific deletion of Atf6α altered the pulmonary macrophage composition, expanding CD11b+ subpopulations with dual polarized CD38+ CD206+ expressing macrophages. Compositional changes were associated with an aggravation of fibrogenesis including increased myofibroblast and collagen deposition. A further mechanistic ex vivo investigation revealed that ATF6α was required for CHOP induction and the death of bone marrow-derived macrophages. Overall, our findings suggest a detrimental role for the ATF6α-deficient CD11b+ macrophages which had altered function during lung injury and fibrosis.


Asunto(s)
Fibrosis Pulmonar Idiopática , Lesión Pulmonar , Ratones , Animales , Lesión Pulmonar/metabolismo , Factor de Transcripción Activador 6/metabolismo , Ratones Endogámicos C57BL , Macrófagos/metabolismo , Pulmón/patología , Fibrosis Pulmonar Idiopática/patología , Fibrosis , Bleomicina/efectos adversos , Bleomicina/metabolismo
3.
Biochem Pharmacol ; 211: 115501, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36921632

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is the representative phenotype of interstitial lung disease where severe scarring develops in the lung interstitium. Although antifibrotic treatments are available and have been shown to slow the progression of IPF, improved therapeutic options are still needed. Recent data indicate that macrophages play essential pro-fibrotic roles in the pathogenesis of pulmonary fibrosis. Historically, macrophages have been classified into two functional subtypes, "M1″ and "M2," and it is well described that "M2″ or "alternatively activated" macrophages contribute to fibrosis via the production of fibrotic mediators, such as TGF-ß, CTGF, and CCL18. However, highly plastic macrophages may possess distinct functions and phenotypes in the fibrotic lung environment. Thus, M2-like macrophages in vitro and pro-fibrotic macrophages in vivo are not completely identical cell populations. Recent developments in transcriptome analysis, including single-cell RNA sequencing, have attempted to depict more detailed phenotypic characteristics of pro-fibrotic macrophages. This review will outline the role and characterization of pro-fibrotic macrophages in fibrotic lung diseases and discuss the possibility of treating lung fibrosis by preventing or reprogramming the polarity of macrophages. We also utilized a systematic approach to review the literature and identify novel and promising therapeutic agents that follow this treatment strategy.


Asunto(s)
Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Humanos , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/patología , Pulmón/patología , Macrófagos/patología , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/patología , Fibrosis
4.
Wound Repair Regen ; 29(4): 548-562, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34107123

RESUMEN

Since the discovery of the myofibroblast over 50 years ago, much has been learned about its role in wound healing and fibrosis. Its origin, however, remains controversial, with a number of progenitor cells being proposed. Macrophage-myofibroblast transition (MMT) is a recent term coined in 2014 that describes the mechanism through which macrophages, derived from circulating monocytes originating in the bone marrow, transformed into myofibroblasts and contributed to kidney fibrosis. Over the past years, several studies have confirmed the existence of MMT in various systems, suggesting that MMT could potentially occur in all fibrotic conditions and constitute a reasonable therapeutic target to prevent progressive fibrotic disease. In this perspective, we examined recent evidence supporting the notion of MMT in both human disease and experimental models across organ systems. Mechanistic insight from these studies and information from in vitro studies is provided. The findings substantiating plausible MMT showcased the co-expression of macrophage and myofibroblast markers, including CD68 or F4/80 (macrophage) and α-SMA (myofibroblast), in fibroblast-like cells. Furthermore, fate-mapping experiments in murine models exhibiting myeloid-derived myofibroblasts in the tissue further provide direct evidence for MMT. Additionally, we provide some evidence from single cell RNA sequencing experiments confirmed by fluorescent in situ hybridisation studies, showing monocyte/macrophage and myofibroblast markers co-expressed in lung tissue from patients with fibrotic lung disease. In conclusion, MMT is likely a significant contributor to myofibroblast formation in wound healing and fibrotic disease across organ systems. Circulating precursors including monocytes and the molecular mechanisms governing MMT could constitute valid targets and provide insight for the development of novel antifibrotic therapies; however, further understanding of these processes is warranted.


Asunto(s)
Monocitos , Miofibroblastos , Animales , Diferenciación Celular , Fibrosis , Humanos , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Miofibroblastos/patología , Cicatrización de Heridas
5.
Methods Mol Biol ; 2299: 291-321, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34028751

RESUMEN

The drug discovery pipeline, from discovery of therapeutic targets through preclinical and clinical development phases, to an approved product by health authorities, is a time-consuming and costly process, where a lead candidates' success at reaching the final stage is rare. Although the time from discovery to final approval has been reduced over the last decade, there is still potential to further optimize and streamline the evaluation process of each candidate as it moves through the different development phases. In this book chapter, we describe our preclinical strategies and overall decision-making process designed to evaluate the tolerability and efficacy of therapeutic candidates suitable for patients diagnosed with fibrotic lung disease. We also describe the benefits of conducting preliminary discovery trials, to aid in the selection of suitable primary and secondary outcomes to be further evaluated and assessed in subsequent internal and external validation studies. We outline all relevant research methodologies and protocols routinely performed by our research group and hope that these strategies and protocols will be a useful guide for biomedical and translational researchers aiming to develop safe and beneficial therapies for patients with fibrotic lung disease.


Asunto(s)
Bleomicina/efectos adversos , Redes Reguladoras de Genes/efectos de los fármacos , Fibrosis Pulmonar/tratamiento farmacológico , Animales , Biología Computacional/métodos , Toma de Decisiones , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos C57BL , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo
6.
Biochem Pharmacol ; 190: 114577, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33887259

RESUMEN

Non-targeted drug delivery systems have several limitations including the decreased bioavailability of the drug, poor stability and rapid clearance in addition to off-target distribution. Cell-specific targeted delivery approaches promise to overcome some of these limitations and enhance therapeutic selectivity. In this review, we aim to discuss cell-specific targeted approachesin the lung at the biochemical and molecular levels. These approaches include;a) directly administered small molecule drugs with intracellular action; b) targeted biologics and synthetic hybrids with extracellular action; c) site activateddrugs; and d) delivery systems.We discuss the pharmaceutical and biochemical parameters that govern the fate of drug molecules at delivery sites while presenting an overview of relevant literature surrounding this area of research and current advancements.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/patología , Pulmón/citología , Mucosa Respiratoria/citología , Animales , Materiales Biocompatibles/administración & dosificación , Portadores de Fármacos/administración & dosificación , Sistemas de Liberación de Medicamentos/tendencias , Humanos , Pulmón/efectos de los fármacos , Pulmón/fisiología , Nanopartículas/administración & dosificación , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/fisiología
8.
Rambam Maimonides Med J ; 12(1)2021 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-33064636

RESUMEN

Diarrhea, an illness of both the developed and developing world, involves the burdensome characteristics of frequent bowel movements, loose stools, and abdominal discomfort. Diarrhea is a long-standing challenge in palliative care and can have a myriad of causes, making symptomatic treatment pertinent when illness evaluation is ongoing, when there is no definitive treatment approach, or when effective treatment cannot be attained. Symptomatic therapy is a common approach in palliative care settings. Bismuth is a suitable agent for symptomatic therapy and can be effectively employed for management of chronic diarrhea. The objective of this narrative review is to examine the role of bismuth in management of diarrheal symptoms. To explore this, PubMed (including Medline) and Embase were used to search the existing literature on bismuth and diarrhea published from 1980 to 2019. It was found that bismuth has potential utility for diarrheal relief in multiple settings, including microscopic colitis, traveler's diarrhea, gastrointestinal infection, cancer, and chemotherapy. It also has great potential for use in palliative care patients, due to its minimal side effects. Overall, the antisecretory, anti-inflammatory, and antibacterial properties of bismuth make it a suitable therapy for symptomatic treatment of diarrhea. The limited range of adverse side effects makes it an appealing option for patients with numerous comorbidities. Healthcare providers can explore bismuth as an adjunct therapy for diarrhea management in an array of conditions, especially in the palliative care setting.

9.
Am J Respir Cell Mol Biol ; 64(2): 235-246, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33253593

RESUMEN

Pulmonary fibrosis is a progressive lung disease characterized by myofibroblast accumulation and excessive extracellular matrix deposition. We sought to investigate the role of FKBP13 (13-kD FK506-binding protein), an endoplasmic reticulum-resident molecular chaperone, in various forms of pulmonary fibrosis. We first characterized the gene and protein expression of FKBP13 in lung biopsy specimens from 24 patients with idiopathic pulmonary fibrosis and 17 control subjects. FKBP13 expression was found to be elevated in the fibrotic regions of idiopathic pulmonary fibrosis lung tissues and correlated with declining forced vital capacity and dyspnea severity. FKBP13 expression was also increased in lung biopsy specimens of patients with hypersensitivity pneumonitis, rheumatoid arthritis, and sarcoidosis-associated interstitial lung disease. We next evaluated the role of this protein using FKBP13-/- mice in a bleomycin model of pulmonary fibrosis. Animals were assessed for lung function and histopathology at different stages of lung injury including the inflammatory (Day 7), fibrotic (Day 21), and resolution (Day 50) phases. FKBP13-/- mice showed increased infiltration of inflammatory cells and cytokines at Day 7, increased lung elastance and fibrosis at Day 21, and impaired resolution of fibrosis at Day 50. These changes were associated with an increased number of cells that stained positive for TUNEL and cleaved caspase 3 in the FKBP13-/- lungs, indicating a heightened cellular sensitivity to bleomycin. Our findings suggest that FKBP13 is a potential biomarker for severity of interstitial lung diseases and that it has a biologically relevant role in protecting mice against bleomycin-induced injury, inflammation, and fibrosis.


Asunto(s)
Enfermedades Pulmonares Intersticiales/metabolismo , Enfermedades Pulmonares Intersticiales/patología , Proteínas de Unión a Tacrolimus/metabolismo , Regulación hacia Arriba/fisiología , Animales , Biomarcadores/metabolismo , Biopsia/métodos , Bleomicina/efectos adversos , Citocinas/metabolismo , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Femenino , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Inflamación/metabolismo , Inflamación/patología , Pulmón , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Regulación hacia Arriba/efectos de los fármacos
10.
Pulm Pharmacol Ther ; 63: 101933, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32750409

RESUMEN

Oral nintedanib is marketed for the treatment of idiopathic pulmonary fibrosis (IPF). While effective slowing fibrosis progression, as an oral medicine nintedanib is limited. To reduce side effects and maximize efficacy, nintedanib was reformulated as a solution for nebulization and inhaled administration. To predict effectiveness treating IPF, the nintedanib pharmacokinetic/pharmacodynamic relationship was dissected. Pharmacokinetic analysis indicated oral-delivered nintedanib plasma exposure and lung tissue partitioning were not dose-proportional and resulting lung levels were substantially higher than blood. Although initial-oral absorbed nintedanib efficiently partitioned into the lung, only a quickly eliminated fraction appeared available to epithelial lining fluid (ELF). Because IPF disease appears to initiate and progress near the epithelial surface, this observation suggests short duration nintedanib exposure (oral portion efficiently partitioned to ELF) is sufficient for IPF efficacy. To test this hypothesis, exposure duration required for nintedanib activity was explored. In vitro, IPF-cellular matrix (IPF-CM) increased primary normal human fibroblast (nHLF) aggregate size and reduced nHLF cell count. IPF-CM also increased nHLF ACTA2 and COL1A expression. Whether short duration (inhalation pharmacokinetic mimic) or continuous exposure (oral pharmacokinetic mimic), nintedanib (1-100 nM) reversed these effects. In vivo, intubated silica produced a strong pulmonary fibrotic response. Once-daily (QD) 0.021, 0.21 and 2.1 mg/kg intranasal (IN; short duration inhaled exposure) and twice-daily (BID) 30 mg/kg oral (PO; long duration oral exposure) showed that at equivalent-delivered lung exposure, QD short duration inhaled nintedanib (0.21 mg/kg IN vs. 30 mg/kg PO) exhibited equivalent-to-superior activity as BID oral (reduced silica-induced elastance, alpha-smooth muscle actin, interleukin-1 beta (IL-1ß) and soluble collagen). Comparatively, the increased inhaled lung dose (2.1 mg/kg IN vs. 30 mg/kg PO) exhibited increased effect by further reducing silica-induced elastance, IL-1ß and soluble collagen. Neither oral nor inhaled nintedanib reduced silica-induced parenchymal collagen. Both QD inhaled and BID oral nintedanib reduced silica-induced bronchoalveolar lavage fluid macrophage and neutrophil counts with oral achieving significance. In summary, pharmacokinetic elements important for nintedanib activity can be delivered using infrequent, small inhaled doses to achieve oral equivalent-to-superior pulmonary activity.


Asunto(s)
Fibrosis Pulmonar Idiopática , Fibroblastos , Humanos , Indoles , Pulmón
11.
Expert Opin Drug Discov ; 15(8): 931-941, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32396021

RESUMEN

INTRODUCTION: Pulmonary fibrosis includes several lung disorders characterized by progressive fibrosis, of which idiopathic pulmonary fibrosis (IPF) is a particularly severe form with a median survival time of 3-5 years after diagnosis. Although numerous compounds have shown efficacy in attenuating pulmonary fibrosis using animal models, only a few compounds have shown their beneficial effects for IPF in clinical trials. Thus, there is an emergent need to improve the preclinical development process to better identify, characterize and select clinically useful targets. AREAS COVERED: In this review, the authors extensively describe current models of pulmonary fibrosis, including rodent models, ex vivo models, and in vitro models. EXPERT OPINION: Based upon our current understanding, improving the identification and characterization of clinically relevant molecules or pathways responsible for progressive fibrotic diseases and use of the appropriate preclinical model system to test these will likely be required to improve the drug development pipeline for pulmonary fibrosis. Combination with appropriate preclinical models with ex vivo (precision-cut lung slices) or in vitro models would be beneficial for high-throughput drug discovery or validation of drug effects.


Asunto(s)
Desarrollo de Medicamentos , Descubrimiento de Drogas , Fibrosis Pulmonar/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Ensayos Analíticos de Alto Rendimiento , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/fisiopatología , Fibrosis Pulmonar/fisiopatología , Índice de Severidad de la Enfermedad , Tasa de Supervivencia
12.
Eur Respir J ; 55(6)2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32165401

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown aetiology, which makes drug development challenging. Single administration of bleomycin directly to the lungs of mice is a widely used experimental model for studying pulmonary fibrogenesis and evaluating the effect of therapeutic antifibrotic strategies. The model works by inducing an early inflammatory phase, which transitions into fibrosis after 5-7 days. This initial inflammation makes therapeutic timing crucial. To accurately assess antifibrotic efficacy, the intervention should inhibit fibrosis without impacting early inflammation.Studies published between 2008 and 2019 using the bleomycin model to investigate pulmonary fibrosis were retrieved from PubMed, and study characteristics were analysed. Intervention-based studies were classified as either preventative (starting <7 days after bleomycin installation) or therapeutic (>7 days). In addition, studies were cross-referenced with current major clinical trials to assess the availability of preclinical rationale.A total of 976 publications were evaluated. 726 investigated potential therapies, of which 443 (61.0%) were solely preventative, 166 (22.9%) were solely therapeutic and 105 (14.5%) were both. Of the 443 preventative studies, only 70 (15.8%) characterised inflammation during the model's early inflammatory phase. In the reported 145 IPF clinical trials investigating 93 compounds/combinations, only 25 (26.9%) interventions had any preclinical data on bleomycin available on PubMed.Since 2008, we observed a shift (from <5% to 37.4%) in the number of studies evaluating drugs in the therapeutic setting in the bleomycin model. While this shift is encouraging, further characterisation of early inflammation and appropriate preclinical therapeutic testing are still needed. This will facilitate fruitful drug development in IPF, and more therapeutic strategies for patients with this devastating disease.


Asunto(s)
Bleomicina , Modelos Animales de Enfermedad , Fibrosis Pulmonar Idiopática , Animales , Fibrosis , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/patología , Pulmón/patología , Ratones
13.
Chest ; 157(5): 1207-1220, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31778676

RESUMEN

Chronic lung disease accounts for a significant global burden with respect to death, disability, and health-care costs. Due to the heterogeneous nature and limited treatment options for these diseases, it is imperative that the cellular and molecular mechanisms underlying the disease pathophysiology are further understood. The lung is a complex organ with a diverse cell population, and each cell type will likely have different roles in disease initiation, progression, and resolution. The effectiveness of a given therapeutic agent may depend on the net effect on each of these cell types. Over the past decade, it has been established that endoplasmic reticulum stress and the unfolded protein response are involved in the development of several chronic lung diseases. These conserved cellular pathways are important for maintaining cellular proteostasis, but their aberrant activation can result in pathology. This review discusses the current understanding of endoplasmic reticulum stress and the unfolded protein response at the cellular level in the development and progression of various chronic lung diseases. We highlight the need for increased understanding of the specific cellular contributions of unfolded protein response activation to these pathologies and suggest that the development of cell-specific targeted therapies is likely required to further decrease disease progression and to promote resolution of chronic lung disease.


Asunto(s)
Estrés del Retículo Endoplásmico/fisiología , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/fisiopatología , Respuesta de Proteína Desplegada , Enfermedad Crónica , Progresión de la Enfermedad , Humanos , Desplegamiento Proteico
14.
Ann Palliat Med ; 8(2): 130-139, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30943737

RESUMEN

BACKGROUND: Home-based palliative care is care of the patient in their home, while doctors and other healthcare providers (HCPs) make visits as required. Family involvement naturally cultivates a relationship between HCPs and the family. Once the patient dies and home-based palliative care ends, this relationship is abruptly terminated, which may be challenging to both the family and the HCPs. The objective of this study was to understand the thoughts and opinions of HCPs and families on their encountered loss of relationship at the end of home-based palliative care. METHODS: Perceptions of 63 participants (32 HCPs and 31 family members) were explored using semi-structured interviews and the qualitative research methodologies of grounded theory. HCPs were interviewed at the Temmy Latner Centre for Palliative Care (TLCPC), a home-based palliative care group of physicians, and 2 hospitals in Toronto, while family members were recruited from TLCPC's records of deceased patients. RESULTS: Six overarching themes, relating to HCP-family relationship dynamics, the experience of loss of relationship, and potential solutions, were derived from the data: (I) home palliative care is intimate; (II) dissatisfaction is experienced with abrupt relationship ending; (III) families benefit from open communication, especially after patient death; (IV) HCPs recognize the insufficiency in bereavement resources; (V) benefits are recognized for a system to ease loss of relationship, and lastly; (VI) challenges with introducing such a system concern HCP. CONCLUSIONS: Overall, families and HCPs do not like the loss of relationship post-patient death, and recognize the potential benefits of an approach that would allow for communication going forward.


Asunto(s)
Aflicción , Muerte , Familia , Personal de Salud , Adulto , Anciano , Femenino , Servicios de Atención de Salud a Domicilio , Humanos , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Cuidados Paliativos
15.
J Food Sci ; 83(2): 499-508, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29377120

RESUMEN

There has been increased interest in the use of dietary ingredients, including prebiotics such as human-milk oligosaccharides (HMOs), as therapeutic strategies for food allergy. Understanding the mechanisms underlying the beneficial effects of HMOs is important to realizing their therapeutic potential. Here we demonstrate that the HMO, 6'-sialyllactose (6'SL) inhibited chemokine (IL-8 and CCL20) release from T-84 and HT-29 cells stimulated with antigen-antibody complex, TNFα or PGE2 ; an effect that was PPARγ dependent and associated with decreased activity of the transcription factors AP-1 and NFκB. In contrast, 2'-fucosyllactose (2'FL) selectively inhibited CCL20 release in response to antigen antibody complex in a PPARγ independent manner. This study reinforces the concept that structurally different oligosaccharides have distinct biological activities and identifies, for the first time, that the HMOs, 6'SL, and 2'FL, modulate human epithelial cell responses related to allergic disease. These findings encourage further investigation of the therapeutic potential of specific HMOs in food allergy. PRACTICAL APPLICATION: This study provides evidence for direct effects of HMOs in addition to their prebiotic role and demonstrates, for the first time, modulation of Ag-IgE complex activation of human epithelial cells that may have important implications for food-allergy. The study also reinforces the concept that structurally different oligosaccharides have distinct biological activities. In determining the composition of infant formula, addition of oligosaccharides with specific structures may provide direct modulation of immune responses and potentially attenuate symptoms or development of food allergy.


Asunto(s)
Complejo Antígeno-Anticuerpo/inmunología , Quimiocinas/inmunología , Células Epiteliales/inmunología , Hipersensibilidad a los Alimentos/inmunología , Leche Humana/química , Oligosacáridos/farmacología , Prebióticos/análisis , Quimiocinas/genética , Células Epiteliales/efectos de los fármacos , Hipersensibilidad a los Alimentos/tratamiento farmacológico , Células HT29 , Humanos , Fórmulas Infantiles/química , Intestinos/efectos de los fármacos , Intestinos/inmunología , Trisacáridos/farmacología
16.
Curr Med Res Opin ; 34(7): 1253-1259, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29231746

RESUMEN

OBJECTIVE: Symptomatic therapy is an intervention centered entirely on symptom management and pain relief. The utilization of charcoal in diarrhea management is a pertinent example of this type of medical care. Diarrhea is an ailment defined as an escalation in the frequency of bowel movements, unformed stool, abdominal discomfort, and pain. These symptoms can be extremely debilitating for patients, and effectuate frustration as well as severely dampening mood and overall well-being. This narrative review aims to explore the use of charcoal in diarrhea management and its possible benefits in alleviating discomfort associated with these symptoms. METHODS: The authors used PubMed, MEDLINE, and Google Scholar searches on recent literature available on the role of activated charcoal in diarrhea management. RESULTS: It was found that the main precursors of diarrhea include drugs and bacterial infection. Activated charcoal has a firm history in its ability to attract and expel ingested toxins from the gastrointestinal tract. It acts to prevent system absorption of these adverse entities, adsorbing them on the surface of its particles, making it a suitable diarrheal treatment. CONCLUSIONS: Diarrhea can present itself alongside a multitude of treatments and conditions, such as chemotherapy, primary malignancy, intestinal, colorectal and pancreatic cancer, bacterial infection, and irritable bowel syndrome, making activated charcoal a potential therapy in these conditions. In comparison, with other common anti-diarrheal treatments, activated charcoal has exceptionally few side-effects. Overall, further research is necessary in order to wholly determine the effectiveness of charcoal in the management of diarrhea.


Asunto(s)
Carbón Orgánico/uso terapéutico , Diarrea/tratamiento farmacológico , Dolor Abdominal/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Diarrea/etiología , Femenino , Humanos , Síndrome del Colon Irritable/complicaciones , Masculino , Cuidados Paliativos/métodos , Neoplasias Pancreáticas/complicaciones , Calidad de Vida
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