Stem cells have emerged as promising therapeutic options for several human diseases, including pulmonary fibrosis (PF). In this study, we investigated the therapeutic effects of adipose tissue-derived mesenchymal stem cells (ADMSCs) in the bleomycin-induced PF model rats and the underlying mechanisms. The PF model rats were generated by intratracheal injections of 5 mg/kg bleomycin sulfate. The ADMSC group rats were generated by injecting 2×10(6) ADMSCs via the tail vein at 0, 12, and 24 h after bleomycin injection. The control, PF, and ADMSC group rats were sacrificed on day 21 after bleomycin injections and the changes in lung histology and the levels of pro-inflammatory cytokines, collagen I, and caveolin-1 (Cav-1), and the activity of the NF-kappaB signaling pathway in the lung tissues was assessed by hematoxylin-eosin staining, ELISA, and western blotting assays. The lung tissues of the PF model rats showed significant infiltration of neutrophils, tissue destruction, and collagen deposition, but these effects were abrogated by the ADMSCs. The levels of pro-inflammatory cytokines such as IL-6, IL-1beta, and TGF-beta1 were elevated in the lung tissues and the bronchoalveolar lavage fluid (BALF) of the bleomycin-induced PF model rats, but these effects were reversed by the ADMSCs. The lung tissues of the PF model rats showed significant downregulation of Cav-1 and significantly higher activation of the pro-inflammatory NF-kappaB pathway. However, administration of the ADMSCs restored the expression levels of Cav-1 and suppressed the NF-kappaB signaling pathway in the lungs of the bleomycin-induced PF model rats. In conclusion, this study demonstrated that the ADMSCs protected against bleomycin-induced PF in the rat model by modulating the Cav-1/NF-kappaB axis.
- MeSH
- bleomycin toxicita MeSH
- cytokiny metabolismus MeSH
- kaveolin 1 metabolismus farmakologie terapeutické užití MeSH
- kolagen metabolismus MeSH
- krysa rodu rattus MeSH
- mezenchymální kmenové buňky * metabolismus MeSH
- NF-kappa B metabolismus MeSH
- plíce MeSH
- plicní fibróza * chemicky indukované terapie metabolismus MeSH
- pneumonie * metabolismus MeSH
- potkani Sprague-Dawley MeSH
- signální transdukce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
We investigated neuronal activity of the medulla oblongata during gastroesophageal reflux-related cough (GERC). A rat model of GERC was generated by perfusing HCl into lower esophagus and inducing cough with citric acid. The HCl group rat was received HCl perfusion without citric acid-induced cough. The saline control rat was perfused with saline instead and cough was induced. Citric acid-induced cough rat was only induced by citric acid. Blank group rats were fed normally. Fos expressions were observed in medulla oblongata nuclei using immunohistochemistry. Manganese-enhanced magnetic resonance imaging (MEMRI) was performed to detect the Mn(2+) signal following intraperitoneal injection of MnCl(2). HCl perfusion and citric acid-induced cough caused Fos expressions in the nucleus of solitary tract (nTS), dorsal motor nucleus of the vagus (DMV), paratrigeminal nucleus (Pa5), and intermediate reticular nucleus (IRt), which was higher than HCl group, saline control group, citric acid-induced cough group, and blank group. A high Mn(2+) signal was also observed in most of these nuclei in model rats, compared with blank group animals. The Mn(2+) signal was also higher in the HCl, saline and citric acid-induced cough group animals, compared with blank group animals. The study showed medulla oblongata neurons were excited in a HCl perfusion and citric acid-induced cough rat model, and nTS, DMV, Pa5 and IRt neurons maybe involved in the cough process and signal integrate.
- MeSH
- gastroezofageální reflux diagnostické zobrazování metabolismus MeSH
- kašel diagnostické zobrazování metabolismus MeSH
- krysa rodu rattus MeSH
- magnetická rezonanční tomografie metody MeSH
- mangan metabolismus MeSH
- medulla oblongata diagnostické zobrazování metabolismus MeSH
- modely nemocí na zvířatech * MeSH
- neurony metabolismus patologie MeSH
- potkani Sprague-Dawley MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted. METHODS: Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: In total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]-positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9-86.9), 72.5% (95% CI: 58.3-84.1), and 75.7% (95% CI: 64.3-84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2-NE), 20.7 (95% CI: 15.8-NE), and 15.4 (95% CI: 8.3-NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%). CONCLUSION: Ceritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity.
- MeSH
- anaplastická lymfomová kináza genetika MeSH
- antitumorózní látky terapeutické užití MeSH
- dospělí MeSH
- genová přestavba MeSH
- kritéria léčebné odpovědi MeSH
- lidé středního věku MeSH
- lidé MeSH
- maximální tolerovaná dávka MeSH
- mladý dospělý MeSH
- nádory jater farmakoterapie genetika sekundární MeSH
- nádory kostí farmakoterapie genetika sekundární MeSH
- nádory mozku farmakoterapie genetika sekundární MeSH
- nádory plic farmakoterapie genetika patologie MeSH
- následné studie MeSH
- nemalobuněčný karcinom plic farmakoterapie genetika patologie MeSH
- omezení příjmu potravy * MeSH
- potraviny * MeSH
- prognóza MeSH
- pyrimidiny terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sulfony terapeutické užití MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
The aim of this study was to investigate the effects of melatonin on oxidative stress, the expression of transient receptor potential melastatin-2 (TRPM2) in guinea pig brains, and the influence of melatonin on oxidative stress in lungs and airway inflammation induced by particulate matter 2.5 (PM2.5). A particle suspension (0.1 g/ml) was nasally administered to the guinea pigs to prepare a PM2.5 exposure model. Cough frequency and cough incubation period were determined through RM6240B biological signal collection and disposal system. Oxidative stress markers, including malondialdehyde (MDA), total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px), in the medulla oblongata were examined through spectrophotometer. Reactive oxygen species (ROS) were detected in the hypoglossal nucleus, cuneate nucleus, Botzinger complex, dorsal vagal complex, and airway through dihydroethidium fluorescence. Hematoxylin-eosin (HE) staining and substance P expression via immunohistochemistry revealed the inflammatory levels in the airway. TRPM2 was observed in the medulla oblongata through immunofluorescence and Western blot. The ultrastructure of the blood-brain barrier and neuronal mitochondria was determined by using a transmission electron microscope. Our study suggests that melatonin treatment decreased PM2.5-induced oxidative stress level in the brains and lungs and relieved airway inflammation and chronic cough. TRPM2 might participate in oxidative stress in the cough center by regulating cough.
- MeSH
- antioxidancia terapeutické užití MeSH
- hematoencefalická bariéra účinky léků patologie MeSH
- kašel chemicky indukované farmakoterapie patologie MeSH
- kationtové kanály TRPM metabolismus MeSH
- látky znečišťující vzduch škodlivé účinky MeSH
- medulla oblongata účinky léků metabolismus MeSH
- melatonin terapeutické užití MeSH
- morčata MeSH
- mozek - chemie účinky léků MeSH
- oxidační stres účinky léků MeSH
- pevné částice škodlivé účinky MeSH
- plíce účinky léků MeSH
- velikost částic MeSH
- zvířata MeSH
- Check Tag
- morčata MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Neuronal activity in the medulla oblongata and neurogenic inflammation of airways were investigated in a guinea pig model induced by repeated intra-esophageal instillation of hydrochloric acid (HCl) after vagotomy. Unilateral vagotomy was performed in the vagotomy group, while a sham-operation was performed in the sham group. Operation was not conducted in sham control group. Airway inflammation was observed with hematoxylin and eosin (HE) staining. C-fos protein was measured by immunohistochemistry (IHC) and Western blot (WB). Substance P was examined by IHC and enzyme-linked immuno sorbent assay (ELISA). Airway microvascular permeability was detected by evans blue dye (EBD) fluorescence. Inflammation of airway was observed in the trachea and bronchi after chronic HCl perfusion into the lower esophagus, and was alleviated after unilateral vagotomy. C-fos expression in the medulla oblongata was lower in the vagotomy group compared to the sham control and sham groups. Substance P-like immunoreactivity (SP-li), concentration and microvascular leakage in airway were lower in the vagotomy group than that in the other groups. Our results suggest that vagotomy improved neurogenic inflammation of airways and decreased neuronal activities, the afferent nerves and neurons in medulla oblongata may be involved in neurogenic inflammation of airways mediated by esophageal-bronchial reflex.
- MeSH
- abnormální reflex MeSH
- aspirační pneumonie chemicky indukované patofyziologie chirurgie MeSH
- ezofágus inervace MeSH
- kapilární permeabilita MeSH
- kyselina chlorovodíková * MeSH
- medulla oblongata metabolismus patofyziologie MeSH
- morčata MeSH
- neurogenní zánět chemicky indukované patofyziologie chirurgie MeSH
- plíce inervace metabolismus MeSH
- protoonkogenní proteiny c-fos metabolismus MeSH
- substance P metabolismus MeSH
- vagotomie * MeSH
- zvířata MeSH
- Check Tag
- morčata MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH