Activation of NF-kB mediates ICAM-1 induction in respiratory cells exposed to an adenovirus-derived vector

Gene transfer to the respiratory tract by replication-deficient adenoviruses is limited by the induction of inflammatory and immune responses. We previously demonstrated that a E1-E3-deleted recombinant adenovirus carrying the expression cassette for the cystic fibrosis gene (Ad.CFTR) upregulates the expression of the pro-inflammatory intercellular adhesion molecule-1 (ICAM-1) both in vitro and in vivo. In the present work we suggest a role for the nuclear factor-kB (NF-kB) in Ad.CFTR-dependent up-regulation of ICAM-1 in respiratory epithelial A549 cells. Specifically, Ad.CFTR induced translocation of NF-kB into the nucleus and binding to the proximal -228/-218 NF-kB consensus sequence on the ICAM-1 promoter. Ad.CFTR also stimulated a 13-fold increase in NF-kB-dependent expression of the CAT reporter gene under the control of a region of the ICAM-1 promoter, including the proximal NF-kB consensus sequence. The Ad.CFTR-dependent increase of ICAM-1 mRNA was abolished by inhibitors of NF-kB, such as N-acetyl-L-cysteine, pyrrolidine dithiocarbamate, parthenolide and the synthetic peptide SN50. All these inhibitors abolished both Ad.CFTR-induced NF-kB DNA binding and transactivating activities. These results indicate a critical role of NF-kB in the pro-inflammatory response elicited by replication-deficient adenoviral vectors in respiratory cells.     

Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors

相似文献   

Conservative management of malignant gastric outlet obstruction syndrome-evidence based evaluation of endoscopic ultrasound-guided gastroentero-anastomosis

Gastric outlet obstruction (GOO) is a clinical syndrome characterized by postprandial vomiting, abdominal pain, bloating and, in advanced cases, by weight loss secondary to inadequate oral intake. This clinical entity may be caused by mechanical obstruction, either benign or malignant, or by motility disorders. In this review we will focus on malignant GOO and on its endoscopic ultrasound (EUS)-guided palliative treatment. The most frequent malignant causes of this syndrome are gastric and locally advanced pancreatic carcinomas; other causes include duodenal or ampullary neoplasms, gastric lymphomas, retroperitoneal lymphadenopathies and, more infrequently, gallbladder and bile duct cancers. Surgery represents the treatment of choice when radical and curative resection is potentially feasible; if the malignant cause is not likely to be completely resected, palliative treatments should be proposed. Palliative treatments for malignant GOO are primarily based on surgical gastro-jejunostomy and endoscopic placement of an enteral self-expanding metal stent. Both treatments are effective; however, endoscopic stent placement is less invasive and it is associated with good short-term results, while surgery provides longer-lasting effects with a lower frequency of reintervention. In the last few years, EUS-guided gastroenterostomy (GE) has been proposed as palliative treatment for malignant GOO. This novel technique consists of the creation of an anastomosis between the gastric lumen and a small bowel loop distal to the malignant obstruction, through the deployment of a lumen-apposing metal stent under EUS-view. EUS-GE has the advantage of being as minimally invasive as enteral stent placement, and of guaranteeing long-term results similar to those of surgery.     

Steroidogenesis,proliferation and apoptosis in bovine granulosa cells: role of tumour necrosis factor-alpha and its possible signalling mechanisms

This study was designed to investigate the presence of bioactive tumour necrosis factor-alpha (TNF-alpha) in bovine fluid collected from small (<5 mm) and large (>8 mm) follicles, as well as the production of the cytokine by the granulosa cells collected from the same type of follicles. Moreover, the effectiveness of 10, 1 and 0.1 ng mL(-1) of human TNF-alpha (hTNF-alpha) in affecting the main parameters of granulosa cell function, progesterone (P4) and oestradiol-17beta (E2) production, cell proliferation and apoptosis, was tested. In addition, the study aimed to determine whether the signalling mechanisms of TNF-alpha in these cells involve cAMP, nitric oxide or prostaglandin E2 (PGE2) and F2alpha (PGF2alpha). It emerged that bioactive TNF-alpha is present in follicular fluid from both types of follicles and can be measured in media conditioned by granulosa cells from large follicles. As for the effects of hTNF-alpha, it inhibits P4 production in cells from both types of follicles and stimulates E2 output in those from small follicles; it does not affect proliferation, but it stimulates granulosa cell apoptosis. Finally, the effects of hTNF-alpha on bovine granulosa cells are not mediated by nitric oxide or cAMP, as neither of these substances were affected by treatment with the cytokine; however, in some way, they could be mediated through PGE2 and PGF2alpha, the production of which was inhibited by TNF-alpha in cells from small follicles.     

Inconclusive Cystic Fibrosis neonatal screening results: long-term psychosocial effects on parents

Aim:  Cystic Fibrosis (CF) Newborn Screening occasionally identifies neonates where a CF diagnosis can neither be confirmed nor excluded. To assess how parents of these infants cope with this ambiguous situation.
Methods:  Parents of 11 children with Ambiguous Diagnosis (group AD) were compared with parents of 11 children diagnosed with CF through neonatal screening [group Cystic Fibrosis Diagnosis (CFD)] and with parents of 11 Healthy Control children (group HC) matched for gender and age.
Results:  The emotional reaction to the inconclusive result was less pronounced in AD than in CFD (p = 0.003), and AD parents considered their infants as healthy as controls. Parents' anxiety about their child's health is stronger in CFD than in AD (p < 0.05) and HC (p < 0.001). Long-term emotional distress was rated similarly in AD and CFD, and greater than in HC (p = 0.0003). The parent/child relationship was less influenced in AD than in the CF group (p = 0.03). Seven AD and CFD parents changed their family planning projects.
Conclusion:  Inconclusive neonatal screening results appear to be understood and associated with lower anxiety levels than CF diagnosis. Concern about the child's health is similar to healthy controls and lower than in parents of CF children.