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BACKGROUND: Autoimmune hepatitis is a chronic inflammatory hepatic disorder with no effective treatment. Mesenchymal stromal cells (MSCs) have emerged as a promising treatment owing to their unique advantages. However, their heterogeneity is hampering use in clinical applications. METHODS: Wharton's jelly derived MSCs (WJ-MSCs) were isolated from 58 human donors using current good manufacturing practice conditions. Gene expression profiles of the WJ-MSCs were analyzed by transcriptome and single-cell RNA-sequencing (scRNA-seq), and subsequent functional differences were assessed. Expression levels of programmed death-ligand 1 (PD-L1) were used as an indicator to screen WJ-MSCs with varied immunomodulation activities and assessed their corresponding therapeutic effects in a mouse model of concanavalin A-induced autoimmune hepatitis. RESULTS: The 58 different donor-derived WJ-MSCs were grouped into six gene expression profile clusters. The gene in different clusters displayed obvious variations in cell proliferation, differentiation bias, trophic factor secretion, and immunoregulation. Data of scRNA-seq revealed four distinct WJ-MSCs subpopulations. Notably, the different immunosuppression capacities of WJ-MSCs were positively correlated with PD-L1 expression. WJ-MSCs with high expression of PD-L1 were therapeutically superior to WJ-MSCs with low PD-L1 expression in treating autoimmune hepatitis. CONCLUSION: PD-L1 expression levels of WJ-MSCs could be regarded as an indicator to choose optimal MSCs for treating autoimmune disease. These findings provided novel insights into the quality control of MSCs and will inform improvements in the therapeutic benefits of MSCs.
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Hepatitis Autoinmune , Hepatopatías , Células Madre Mesenquimatosas , Gelatina de Wharton , Animales , Ratones , Humanos , Cordón Umbilical , Hepatitis Autoinmune/genética , Hepatitis Autoinmune/terapia , Hepatitis Autoinmune/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Células Madre Mesenquimatosas/metabolismo , Diferenciación Celular , Proliferación Celular , Células CultivadasRESUMEN
BACKGROUND: The coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic with over 627 million cases and over 6.5 million deaths. It was reported that smoking-related chronic obstructive pulmonary disease (COPD) might be a crucial risk for COVID-19 patients to develop severe condition. As cigarette smoke (CS) is the major risk factor for COPD, we hypothesize that barrier dysfunction and an altered cytokine response in CS-exposed airway epithelial cells may contribute to increased SARS-CoV-2-induced immune response that may result in increased susceptibility to severe disease. The aim of this study was to evaluate the role of CS on SARS-CoV-2-induced immune and inflammatory responses, and epithelial barrier integrity leading to airway epithelial damage. METHODS: Primary human airway epithelial cells were differentiated under air-liquid interface culture. Cells were then exposed to cigarette smoke medium (CSM) before infection with SARS-CoV-2 isolated from a local patient. The infection susceptibility, morphology, and the expression of genes related to host immune response, airway inflammation and damages were evaluated. RESULTS: Cells pre-treated with CSM significantly caused higher replication of SARS-CoV-2 and more severe SARS-CoV-2-induced cellular morphological alteration. CSM exposure caused significant upregulation of long form angiotensin converting enzyme (ACE)2, a functional receptor for SARS-CoV-2 viral entry, transmembrane serine protease (TMPRSS)2 and TMPRSS4, which cleave the spike protein of SARS-CoV-2 to allow viral entry, leading to an aggravated immune response via inhibition of type I interferon pathway. In addition, CSM worsened SARS-CoV-2-induced airway epithelial cell damage, resulting in severe motile ciliary disorder, junctional disruption and mucus hypersecretion. CONCLUSION: Smoking led to dysregulation of host immune response and cell damage as seen in SARS-CoV-2-infected primary human airway epithelia. These findings may contribute to increased disease susceptibility with severe condition and provide a better understanding of the pathogenesis of SARS-CoV-2 infection in smokers.
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COVID-19 , Fumar Cigarrillos , Enfermedad Pulmonar Obstructiva Crónica , Humanos , SARS-CoV-2 , Sistema RespiratorioAsunto(s)
Leucemia Promielocítica Aguda , Trombocitemia Esencial , Humanos , Trombocitemia Esencial/genética , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Translocación Genética , Evolución Clonal/genéticaRESUMEN
Since most current studies have focused on exploring how phagocyte internalization of drug-loaded nanovesicles by macrophages would affect the function and therapeutic effects of infiltrated neutrophils or monocytes, research has evaluated the specificity of the inhaled nanovesicles for targeting various phagocytes subpopulations. In this study, liposomes with various charges (including neutral (L1), anionic (L2), and cationic at inflammatory sites (L3)) were constructed to investigate how particle charge determined their interactions with key phagocytes (including macrophages and neutrophils) in acute lung injury (ALI) models and to establish correlations with their biofate and overall anti-inflammatory effect. Our results clearly indicated that neutrophils were capable of rapidly sequestering L3 with a 3.2-fold increase in the cellular liposome distribution, compared to that in AMs, while 70.5% of L2 were preferentially uptaken by alveolar macrophages (AMs). Furthermore, both AMs and the infiltrated neutrophils performed as the potential vesicles for the inhaled liposomes to prolong their lung retention in ALI models, whereas AMs function as sweepers to recognize and process liposomes in the healthy lung. Finally, inhaled roflumilast-loaded macrophage or neutrophil preferential liposomes (L2 or L3) exhibited optimal anti-inflammatory effect because of the decreased AMs phagocytic capacity or the prolonged circulation times of neutrophils. Such findings will be beneficial in exploiting a potential pathway to specifically manipulate lung phagocyte functions in lung inflammatory diseases where these cells play crucial roles.
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Lesión Pulmonar Aguda , Enfermedades Pulmonares , Neumonía , Humanos , Neutrófilos , Liposomas/metabolismo , Pulmón/metabolismo , Macrófagos/metabolismo , Neumonía/tratamiento farmacológico , Lesión Pulmonar Aguda/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/metabolismoRESUMEN
BACKGROUND: Both obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) are prevalent within obese individuals. We aimed to investigate the effects of intermittent hypoxia (IH), a clinical feature of OSA, on hepatic expression of fatty acid translocase (CD36) in relation to liver injury in lean and diet-induced obese mice. METHODS: Four-week-old male C57BL/6J mice were randomized to standard diet (SD) or high fat (HF) diet groups. At 13-week-old, all mice were exposed to either air or IH (IH30; thirty hypoxic episodes per hour) for four weeks. We assessed liver injury through lipid profile, oxidative and inflammatory stress, histological scoring and hepatic CD36 expression. RESULTS: In lean mice, IH elevated serum and hepatic triglyceride and free fatty acid (FFA) levels, in line with upregulation of hepatic CD36 expression and myeloperoxidase (MPO)-positive cells in support of inflammatory infiltrates along with increase in serum malondialdehyde (MDA), C-X-C motif chemokine ligand 1(CXCL-1) and monocyte chemoattractant protein-1 (MCP-1). In diet-induced obese mice, an increase in hepatic alanine transaminase (ALT) activity, serum and hepatic levels of lipid parameters and inflammatory markers, serum MDA level, hepatic expressions of CD36 and α-smooth muscle actin (α-SMA), and MPO-positive cells was observed. IH potentiated hepatic ALT activity, serum CXCL-1 and hepatic interleukin-6 (IL-6), in line with inflammatory infiltrates, but paradoxically, reduced hepatic FFA level and hepatic CD36 expression, compared to obese mice without IH exposure. However, IH further augmented diet-induced liver steatosis and fibrosis as shown by histological scores. CONCLUSION: This study contributes to support that IH featuring OSA may lead to liver injury via differential regulation of hepatic CD36 expression in lean and diet-induced obese mice.
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Hígado , Apnea Obstructiva del Sueño , Masculino , Ratones , Animales , Ratones Obesos , Ratones Endogámicos C57BL , Hígado/patología , Hipoxia/metabolismo , Hipoxia/patología , Dieta Alta en Grasa/efectos adversos , Triglicéridos/metabolismo , Ácidos Grasos/metabolismoRESUMEN
Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in nigrostriatal and cortical brain regions associated with pathogenic α-synuclein (αSyn) aggregate/oligomer accumulation. LRRK2 hyperactivity is a disease-modifying therapeutic target in PD. However, LRRK2 inhibition may be associated with peripheral effects, albeit with unclear clinical consequences. Here, we significantly reduced αSyn oligomer accumulation in mouse striatum through long-term LRRK2 inhibition using GNE-7915 (specific brain-penetrant LRRK2 inhibitor) without causing adverse peripheral effects. GNE-7915 concentrations in wild-type (WT) mouse sera and brain samples reached a peak at 1 h, which gradually decreased over 24 h following a single subcutaneous (100 mg/kg) injection. The same dose in young WT and LRRK2R1441G mutant mice significantly inhibited LRRK2 kinase activity (Thr73-Rab10 and Ser106-Rab12 phosphorylation) in the lung, which dissipated by 72 h post-injection. 14-month-old mutant mice injected with GNE-7915 twice weekly for 18 weeks (equivalent to ~13 human years) exhibited reduced striatal αSyn oligomer and cortical pSer129-αSyn levels, correlating with inhibition of LRRK2 hyperactivity in brain and lung to WT levels. No GNE-7915-treated mice showed increased mortality or morbidity. Unlike reports of abnormalities in lung and kidney at acute high doses of LRRK2 inhibitors, our GNE-7915-treated mice did not exhibit swollen lamellar bodies in type II pneumocytes or abnormal vacuolation in the kidney. Functional and histopathological assessments of lung, kidney and liver, including whole-body plethysmography, urinary albumin-creatinine ratio (ACR), serum alanine aminotransferase (ALT) and serum interleukin-6 (inflammatory marker) did not reveal abnormalities after long-term GNE-7915 treatment. Long-term inhibition of mutant LRRK2 hyper-kinase activity to physiological levels presents an efficacious and safe disease-modifying therapy to ameliorate synucleinopathy in PD.
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With the current epidemic of obesity worldwide, the prevalence of various obesity-related diseases is constantly increasing. Obesity remains the strongest phenotypic risk factor in both obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD). In OSA, intermittent hypoxia-reoxygenation and sleep fragmentation, as a result of recurrent episodes of upper airway obstruction during sleep, may give rise to a plethora of metabolic derangements downstream. Intermittent hypoxia (IH) is postulated to be an important mechanistic trigger for potential systemic impact on organs or tissues in OSA, and has served as a useful experimental model for seeking evidence for downstream effects of OSA. This narrative review focuses on the clinical association between OSA and NAFLD, and the role of IH in the progression of NAFLD in lean and diet-induced obese animal models. Understanding the roles of obesity and IH on NAFLD would advance our limited knowledge on the potential health consequences of OSA, a disease which is afflicting more and more people globally, and also in devising effective therapeutic strategies for this progressively common liver condition.
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Enfermedad del Hígado Graso no Alcohólico , Apnea Obstructiva del Sueño , Animales , Humanos , Hipoxia/complicaciones , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Obesidad/complicaciones , Factores de RiesgoRESUMEN
Particulate matter with aerodynamic diameter not larger than 2.5 µm (PM2.5) escalated the risk of respiratory diseases. Mitochondrial dysfunction may play a pivotal role in PM2.5-induced airway injury. However, the potential effect of PM2.5 on mitochondrial permeability transition pore (mPTP)-related airway injury is still unknown. This study aimed to investigate the role of mPTP in PM2.5-induced mitochondrial dysfunction in airway epithelial cells in vitro. PM2.5 significantly reduced cell viability and caused apoptosis in BEAS-2B cells. We also found PM2.5 caused cellular and mitochondrial morphological alterations, evidenced by the disappearance of mitochondrial cristae, mitochondrial swelling, and the rupture of the outer mitochondrial membrane. PM2.5 induced mPTP opening via upregulation of voltage-dependent anion-selective channel (VDAC), leading to deprivation of mitochondrial membrane potential, increased mitochondrial reactive oxygen species (ROS) generation and intracellular calcium level. PM2.5 suppressed mitochondrial respiratory function by reducing basal and maximal respiration, and ATP production. The mPTP targeting compounds cyclosporin A [CsA; a potent inhibitor of cyclophilin D (CypD)] and VBIT-12 (a selective VDAC1 inhibitor) significantly inhibited PM2.5-induced mPTP opening and apoptosis, and preserved mitochondrial function by restoring mitochondrial membrane potential, reducing mitochondrial ROS generation and intracellular calcium content, and maintaining mitochondrial respiration function. Our data further demonstrated that PM2.5 caused reduction in nuclear expressions of PPARγ and PGC-1α, which were reversed in the presence of CsA. These findings suggest that mPTP might be a potential therapeutic target in the treatment of PM2.5-induced airway injury.
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Proteínas de Transporte de Membrana Mitocondrial , Poro de Transición de la Permeabilidad Mitocondrial , Células Epiteliales/metabolismo , Potencial de la Membrana Mitocondrial , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Material Particulado/metabolismo , Material Particulado/toxicidadRESUMEN
BACKGROUND: Orosomucoid 1-like protein 3 (ORMDL3), a transmembrane protein localized in the endoplasmic reticulum (ER), has been genetically associated with chronic obstructive pulmonary disease (COPD), in addition to childhood-onset asthma. However, the functional role of ORMDL3 in the pathogenesis of COPD is still unknown. OBJECTIVE: Because cigarette smoke is the major risk factor for COPD, we aimed to investigate the role of ORMDL3 in cigarette smoke-induced human airway smooth muscle cell (HASMC) injury. METHODS: The mRNA and protein expression of ORMDL3 was examined in HASMCs from nonsmokers and smokers without or with COPD. Knockdown of ORMDL3 in primary healthy HASMCs was performed using small interfering RNA before exposure to cigarette smoke medium (CSM) for 24 hours. Inflammatory, proliferative/apoptotic, ER stress, and mitochondrial markers were evaluated. RESULTS: Elevation of ORMDL3 mRNA and protein expression was observed in HASMCs of smokers without or with COPD. CSM caused significant upregulation of ORMDL3 expression in healthy nonsmokers. ORMDL3 knockdown regulated CSM-induced inflammation, cell proliferation, and apoptosis. Silencing ORMDL3 led to reduction of CSM-induced ER stress via inhibition of unfolded protein response pathways such as activating transcription factor 6 and protein kinase RNA-like ER kinase. ORMDL3 was also involved in CSM-induced mitochondrial dysfunction via the mitochondrial fission process. CONCLUSIONS: We report the induction of ORMDL3 in HASMCs after cigarette smoke exposure. ORMDL3 may mediate cigarette smoke-induced activation of unfolded protein response pathways during airway smooth muscle cell injury.
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Asma , Fumar Cigarrillos , Enfermedad Pulmonar Obstructiva Crónica , Asma/metabolismo , Niño , Fumar Cigarrillos/efectos adversos , Estrés del Retículo Endoplásmico , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Miocitos del Músculo Liso/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/genética , ARN Mensajero/metabolismo , NicotianaRESUMEN
Chronic obstructive pulmonary disease (COPD) is among the leading causes of death worldwide, and is characterized by persistent respiratory symptoms and airflow limitation due to chronic airway inflammation. Cigarette smoking is a major risk factor for COPD. This study aims to determine the therapeutic effects of polysaccharides extracted from Dendrobium officinale (DOPs), a valuable traditional Chinese Medicinal herb, on cigarette smoke (CS)-induced airway inflammation in a rat passive smoking model. Male Sprague-Dawley rats were exposed to CS or sham air (SA) as control for a 56-day period. On Day 29, rats were subdivided and given water, DOPs or N-acetylcysteine (NAC) via oral gavage on a daily basis for the remaining duration. DOPs reduced CS-induced oxidative stress as evidenced by reducing malondialdehyde (MDA) levels in the lung. DOPs also exerted potent anti-inflammatory properties as evidenced by a reduction in the number of lymphocytes and monocytes in serum, significantly attenuating infiltration of inflammatory cells in lung tissue, as well as pro-inflammatory mediators in serum, bronchoalveolar lavage (BAL) and lung. Additionally, DOPs inhibited the CS-induced activation of ERK, p38 MAPK and NF-κB signaling pathways. These findings suggest that DOPs may have potentially beneficial effects in limiting smoking-related lung oxidative stress, and inflammation mediated via the inhibition of MAPK and NF-κB signaling pathways in smokers, without or with COPD.
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Antioxidantes/farmacología , Dendrobium , Pulmón/efectos de los fármacos , Extractos Vegetales/farmacología , Neumonía/prevención & control , Polisacáridos/farmacología , Humo/efectos adversos , Productos de Tabaco/efectos adversos , Animales , Antioxidantes/aislamiento & purificación , Dendrobium/química , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Masculino , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Extractos Vegetales/aislamiento & purificación , Neumonía/etiología , Neumonía/inmunología , Neumonía/metabolismo , Polisacáridos/aislamiento & purificación , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
BACKGROUND AND OBJECTIVE: Invasive fungal disease (IFD) is associated with a high mortality for patients with hematological malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed not only to develop a proven/probable IFD risk-scoring model but to identify high-risk populations that would benefit from anti-fungal prophylaxis. METHODS: Data from the China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study were retrieved, and all patients (n = 1053) undergoing allo-HSCT were randomly divided into the training set (n = 685) for model development and the validation set (n = 368) for model verification. A weighted risk score for proven or probable IFD was established through multivariate logistic regression analysis. RESULTS: The study population had a mean age of 28.95 years and the majority underwent myeloablative transplantation in complete remission 1 (53.4%). Five risk factors of IFD were identified, namely neutropenia lasting longer than 14 days, corticosteroid use, diabetes, haploidentical donor, and unrelated donor. Based on the risk score for IFD, the patients were categorized into three groups: low risk (score 0-4, 1.5%-4.0%), intermediate risk (score 5-8, 9.8%), and high risk (score>8, 24.7%-14.0%). Anti-fungal prophylaxis may provide benefits for patients with intermediate (8.5% vs. 18.5%, P = .0085) or high risk (19.4% vs. 30.8%, P = .4651) but not low risk (2.1% vs. 3.8%, P = .6136) of IFD. CONCLUSION: A practical weighted risk score for IFD in patients receiving allo-HSCT was established, which can aid decision-making regarding the administration of anti-fungal prophylaxis.
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Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Infecciones Fúngicas Invasoras , Adulto , Antifúngicos/uso terapéutico , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/epidemiología , Infecciones Fúngicas Invasoras/prevención & control , Factores de RiesgoRESUMEN
Asthma and chronic obstructive pulmonary disease (COPD) are obstructive lung diseases which are characterized by chronic inflammation and an increase in mucus production, and are highly prevalent conditions. Despite recent advances and multiple available therapies, there remains a significant unmet medical need. Over the past 40 years, the introduction of new classes of safe and effective therapy is insufficient. In spite of the high burden of asthma and COPD among patients, there are fewer new approved therapies in comparison to cardiovascular, metabolic and neurological diseases due to few drug candidates and a higher failure rate in the development of respiratory medicine. Lung diseases are amongst the leading causes of death globally with asthma being one of the most prevalent respiratory diseases, which affects people of all ages but, despite effective therapies available, many patients are poorly controlled and have a low quality of life. COPD is currently ranked as the fourth cause of death worldwide and predicted to become the third leading cause of death in 2030. The development of more effective treatments is urgently needed in order to reduce the high mortality rate and the enormous suffering from asthma and COPD. Various inhalation devices with different classes of medications are the foundation as therapies in both asthma and COPD. This article gives a comprehensive review of the promising inhaled therapies in the treatment of asthma and COPD. However, the lack of disease control in asthma and COPD patients may be due to numerous reasons. The association between non-adherence to guidelines on the part of the health care provider and poor inhalation technique and/or non-adherence to the prescribed treatment plan by the patients is common. It is therefore essential to discuss the different delivery systems and the methods used in asthma and COPD patients.
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Asma , Enfermedad Pulmonar Obstructiva Crónica , Administración por Inhalación , Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Calidad de VidaRESUMEN
AIMS: The 18 kDa translocator protein (TSPO) - also known as peripheral benzodiazepine receptor, is found to be expressed in lung epithelium and pneumocytes, which is closely associated with the mitochondrial permeability transition pore (mPTP) and apoptosis. Cigarette smoking, a key risk factor for the development of chronic obstructive pulmonary disease (COPD), is known to induce apoptosis. We aimed to investigate TSPO subcellular localization and to examine whether cigarette smoke medium (CSM) induce apoptosis via TSPO in airway epithelial cells. MAIN METHODS: TSPO subcellular localization and expression were evaluated using immunofluorescent staining and Western blot analysis respectively. TSPO ligands either PK 11195 (a specific antagonist) or AC-5216 (a specific agonist) were pre-incubated in human bronchial epithelial cells before treating with 2% CSM for measurements of apoptotic cells, mitochondrial membrane potential (ΔΨm), cytoplasmic/mitochondrial reactive oxygen species (ROS) and inflammatory marker interleukin (IL)-8 respectively. KEY FINDINGS: TSPO was localized around the nucleus and overlapped with mitochondria in BEAS-2B cells. CSM caused an increase in apoptotic cells along with elevation of TSPO protein expression. Pretreatment of PK 11195 suppressed while AC-5216 potentiated CSM-induced apoptosis, collapse of ΔΨm, elevation of cytoplasmic/mitochondrial ROS levels and IL-8 release. In support, knockdown of TSPO caused a significant suppression of CSM-induced IL-8 release in BEAS-2B cells. SIGNIFICANCE: The findings suggest that TSPO may play a crucial role in the regulation of cigarette smoke-induced mitochondrial dysfunction via mPTP. Therefore, the development of specific TSPO antagonists like PK11195 may be beneficial to combat smoking-related diseases, such as COPD.
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Apoptosis/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Receptores de GABA/metabolismo , Humo/efectos adversos , Bronquios/citología , Línea Celular , Células Epiteliales/patología , Humanos , Isoquinolinas/farmacología , Mitocondrias/patología , Poro de Transición de la Permeabilidad Mitocondrial/metabolismo , Purinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , NicotianaRESUMEN
BACKGROUND: Cigarette smoke (CS)-induced build-up of oxidative stress is the leading cause of chronic obstructive pulmonary disease (COPD). Monoamine oxidases (MAOs) are novel sources of reactive oxygen species (ROS) due to the production of hydrogen peroxide (H2O2). However, it remains unclear whether MAO signaling is involved in CS-induced oxidative stress in vivo. This study aimed at investigating the impact of selegiline, a selective MAO-B inhibitor, on CS-induced lung oxidative stress and inflammation in vivo and its underlying mechanism. METHODS: Sprague Dawley rats were randomly divided into four groups: saline plus sham air (Saline/air), saline plus cigarette smoke (Saline/CS), selegiline plus sham air (Slg/air) and selegiline plus cigarette smoke (Slg/CS). Rats from Saline/air and Saline/CS groups were intraperitoneally injected with saline (2 mL/kg body weight) while rats from Slg/air and Slg/CS groups were injected with selegiline (2 mg/kg body weight) about 30 min prior to exposure daily. The Saline/air and Slg/air groups were exposed to atmospheric air while the Saline/CS and Slg/CS groups were exposed to mainstream CS generated from the whole body inExpose smoking system (SCIREQ, Canada) for twice daily (each for 1 hour with 20 cigarettes). After 7 days, rats were sacrificed to collect bronchoalveolar lavage (BAL) and lung tissues for the measurement of oxidative/anti-oxidative and inflammatory/anti-inflammatory makers respectively. RESULTS: CS caused significant elevation of MAO-B activity, reduction of total antioxidant capacity (T-AOC) and rGSH/GSSG ratio, and enhancement of superoxide dismutase (SOD) activity in rat lung. Selegiline significantly only reversed CS-induced elevation of MAO-B activity and reduction of rGSH/GSSG ratio. The CS-induced elevation of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) expression via nuclear factor erythroid 2-related factor 2 (Nrf2) was also reversed by selegiline. Despite of CS-induced increase in total cell counts, especially the number of macrophages, selegiline had no effect. Selegiline attenuated CS-induced elevation of pro-inflammatory mediators (CINC-1, MCP-1 and IL-6) and restored CS-induced reduction of anti-inflammatory mediator IL-10 in BAL, which was driven through MAPK and NF-κB. CONCLUSIONS: Inhibition of MAO-B may provide a promising therapeutic strategy for CS-mediated oxidative stress and inflammation in acute CS-exposed rat lungs.
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Chronic obstructive pulmonary disease (COPD), characterized by oxidative stress and inflammation, is one of the leading causes of death worldwide, in which cigarette smoke (CS) is the major risk factor. Dendrobium officinale polysaccharides (DOPs) are the main active ingredients extracted from Dendrobium officinale, which have been reported to have antioxidant and anti-inflammatory activity as well as inhibition of mucin gene expression. This study is aimed at investigating the effect of DOPs on CS-induced mucus hypersecretion and viscosity in vitro and in vivo. For in vitro study, primary normal human bronchial epithelial cells (HBECs) differentiated at the air-liquid interface (ALI) culture for 28 days were stimulated with cigarette smoke medium (CSM) in the absence or presence of various concentrations of DOPs or N-acetylcysteine (NAC) for 24 hours. For in vivo study, male Sprague-Dawley rats were randomized to sham air (SA) as control group or CS group for 56 days. At day 29, rats were subdivided and given water as control, DOPs, or NAC as positive control as a mucolytic drug via oral gavage for the remaining duration. Samples collected from apical washing, cell lysates, bronchoalveolar lavage (BAL), and lung tissues were evaluated for mucin gene expression, mucus secretion, and viscosity. DOPs ameliorated the CS-induced mucus hypersecretion and viscosity as shown by the downregulation of MUC5AC mRNA, MUC5AC secretary protein, and mucus viscosity via inhibition of mucus secretory granules in both in vitro and in vivo models. DOPs produced its effective effects on the CS-induced mucus hypersecretion and viscosity via the inhibition of the mucus secretory granules. These findings could be a starting point for considering the potential role of DOPs in the management of the smoking-mediated COPD. However, further research is needed.
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Fumar Cigarrillos/efectos adversos , Dendrobium/química , Moco/metabolismo , Polisacáridos/farmacología , Animales , Células Epiteliales/metabolismo , Células Epiteliales/patología , Células Epiteliales/ultraestructura , Receptores ErbB/metabolismo , Células Caliciformes/patología , Humanos , Hiperplasia , Masculino , Ratas Sprague-Dawley , Tráquea/patología , Tráquea/ultraestructura , ViscosidadRESUMEN
PURPOSE: The role of antithymocyte globulin (ATG) in preventing acute graft-versus-host disease (aGVHD) after HLA-matched sibling donor transplantation (MSDT) is still controversial. PATIENTS AND METHODS: We performed a prospective, multicenter, open-label, randomized controlled trial (RCT) across 23 transplantation centers in China. Patients ages 40-60 years with standard-risk hematologic malignancies with an HLA-matched sibling donor were randomly assigned to an ATG group (4.5 mg/kg thymoglobulin plus cyclosporine [CsA], methotrexate [MTX], and mycophenolate mofetil [MMF]) and a control group (CsA, MTX, and MMF). The primary end point of this study was grade 2-4 aGVHD on day 100. RESULTS: From November 2013 to April 2018, 263 patients were enrolled. The cumulative incidence rate of grade 2-4 aGVHD was significantly reduced in the ATG group (13.7%; 95% CI, 13.5% to 13.9%) compared with the control group (27.0%; 95% CI, 26.7% to 27.3%; P = .007). The ATG group had significantly lower incidences of 2-year overall chronic GVHD (27.9% [95% CI, 27.6% to 28.2%] v 52.5% [95% CI, 52.1% to 52.9%]; P < .001) and 2-year extensive chronic GVHD (8.5% [95% CI, 8.4% to 8.6%] v 23.2% [95% CI, 22.9% to 23.5%]; P = .029) than the control group. There were no differences between the ATG and control groups with regard to cytomegalovirus reactivation, Epstein-Barr virus reactivation, 3-year nonrelapse mortality (NRM), 3-year cumulative incidence of relapse (CIR), 3-year overall survival, or 3-year leukemia-free survival. Three-year GVHD relapse-free survival was significantly improved in the ATG group (38.7%; 95% CI, 29.9% to 47.5%) compared with the control group (24.5%; 95% CI, 16.9% to 32.1%; P = .003). CONCLUSION: Our study is the first prospective RCT in our knowledge to demonstrate that ATG can effectively decrease the incidence of aGVHD after MSDT in the CsA era without affecting the CIR or NRM.
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Suero Antilinfocítico/administración & dosificación , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Adulto , Ciclosporina/administración & dosificación , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Hermanos , Donantes de TejidosRESUMEN
BACKGROUND: The introduction of mold-active antifungal drugs has led clinicians to reconsider the use of fluconazole for preventing invasive fungal disease (IFD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study of recipients of allo-HSCT, we evaluated the effects of different antifungal prophylaxes on the incidence of IFD at different times after transplantation. METHODS: Among the 1,401 patients registered in the prospective China Assessment of Antifungal Therapy in Haematological Disease (CAESAR) study database, there were 661 eligible patients who received primary antifungal prophylaxis. The incidence of IFD at different times after transplantation (early, late, and very late) and overall survival were compared for patients who received different drugs. RESULTS: The overall incidence of probable IFD was 7.0% in the fluconazole group, 12.6% in the itraconazole group, 1.4% in the voriconazole group, and 5.2% in the micafungin group (P=0.0379). However, the four groups had no significant differences in early, late, or very late IFD. The risk factors associated with IFD were neutropenia for more than 14 days, age greater than 18 years, and receipt of transplantation from an alternative (unrelated and haploidentical) donor (P<0.05). Sub-group analysis of alternative donors indicated that the efficacy of fluconazole was similar to the other three drugs in preventing early IFD. CONCLUSIONS: Our results suggest that the efficacy of fluconazole is similar to that of mold-active drugs in preventing early IFD in HSCT patients, even in high-risk patients receiving transplantation from alternative donors. Further prospective randomized studies are needed to confirm this conclusion.
RESUMEN
Nanocrystals (NCs) have been introduced for use in pulmonary delivery in recent decades. Although the deposition and bioavailability have been extensively studied, little is known about the biofate, which influences the drug release and absorption process of NCs. In this study, we fabricated three different sized curcumin NCs by adjusting the parameters of mill machine using a wet milling method and studied the size effect on pulmonary absorption. The small nanocrystals (NC-S, 246.16⯱â¯21.98â¯nm) exhibited a faster dissolution rate and higher diffusion percentage in vitro compared with middle (NC-M, 535.26⯱â¯50.33â¯nm) and large nanocrystals (NC-L, 1089.53⯱â¯194.34â¯nm). Multiple particle tracking experiments revealed that NC-S had larger mean squared displacement during diffusion in simulated mucus of 0.5% hydroxyethyl cellulose solution. Moreover, enhanced cellular uptake and transport efficiency were achieved by NC-S in Calu-3 cells and an air-liquid interface culturing model. NCs were mainly absorbed in the dissolved drug form, as assessed by using the Förster resonance energy transfer (FRET) technique. In vivo lung retention and distribution revealed that few smaller sized nanocrystals were retained in the lung after intratracheal administration. The pharmacokinetic study showed that the AUC(0-t) values of small sized nanocrystals were 1.75- and 3.32-fold greater than NC-M and NC-L, respectively. In conclusion, this study demonstrated that smaller sized nanocrystals were more easily absorbed into the blood system by increasing the dissolution rate.
Asunto(s)
Curcumina/metabolismo , Curcumina/farmacocinética , Sistemas de Liberación de Medicamentos , Pulmón/metabolismo , Nanopartículas/química , Mucosa Respiratoria/metabolismo , Animales , Células Cultivadas , Curcumina/química , Liberación de Fármacos , Humanos , Pulmón/química , Masculino , Tamaño de la Partícula , Ratas , Ratas Sprague-Dawley , Mucosa Respiratoria/química , Solubilidad , Propiedades de Superficie , Distribución TisularRESUMEN
Pulmonary delivery of active drugs has been applied for the treatment of obstructive lung diseases, including asthma, chronic obstructive pulmonary disease and cystic fibrosis, for several decades and has achieved progress in symptom management by bronchodilator inhalation. However, substantial progress in anti-inflammation, prevention of airway remodeling and disease progression is limited, since the majority of the formulation strategies focus only on particle deposition, which is insufficient for pulmonary delivery of the drugs. The lack of knowledge on lung absorption barriers in obstructive lung diseases and on pathogenesis impedes the development of functional formulations by rational design. In this review, we describe the physiological structure and biological functions of the barriers in various regions of the lung, review the pathogenesis and functional changes of barriers in obstructive lung diseases, and examine the interaction of these barriers with particles to influence drug delivery efficiency. Subsequently, we review rational particle design for overcoming lung barriers based on excipients selection, particle size and surface properties, release properties and targeting ability. Additionally, useful particle fabrication strategies and commonly used drug carriers for pulmonary delivery in obstructive lung diseases are proposed in this article.