Cystic Fibrosis from Laboratory to Bedside: The Role of A20 in NF-κB-Mediated Inflammation

Cystic fibrosis (CF) is a lifelong, inflammatory multi-organ disease and the most common lethal, genetic condition in Caucasian populations, with a median survival rate of 41.5 years. Pulmonary disease, characterized by infective exacerbations, bronchiectasis and increasing airway insufficiency is the most serious manifestation of this disease process, currently responsible for over 80% of CF deaths. Chronic dysregulation of the innate immune and host inflammatory response has been proposed as a mechanism central to this genetic condition, primarily driven by the nuclear factor κB (NF-κB) pathway. Chronic activation of this transcription factor complex leads to the production of pro-inflammatory cytokines and mediators such as IL-6, IL-8 and TNF-α. A20 has been described as a central and inducible negative regulator of NF-κB. This intracellular molecule negatively regulates NF-κB-driven pro-inflammatory signalling upon toll-like receptor activation at the level of TRAF6 activation. Silencing of A20 increases cellular levels of p65 and induces a pro-inflammatory state. We have previously shown that A20 expression positively correlates with lung function (FEV1%) in CF. Despite improvement in survival rates in recent years, advancements in available therapies have been incremental. We demonstrate that the experimental use of naturally occurring plant diterpenes such as gibberellin on lipopolysaccharide-stimulated cell lines reduces IL-8 release in an A20-dependent manner. We discuss how the use of a novel bio-informatics gene expression connectivity-mapping technique to identify small molecule compounds that similarly mimic the action of A20 may lead to the development of new therapeutic approaches capable of reducing chronic airway inflammation in CF. 

Greek writers of Roman history : some reflections upon the authorities used by Plutarch and Appianus /

The fons primarius of Plutarch's life of Fabius Maximus. -- The common Greek sources of Plutarch and Appianus for Roman history. -- King Juba's Historia romana.

The life and times of Cleopatra, queen of Egypt; a study in the origin of the Roman empire,

pt. I. Cleopatra and Cæsar.--pt. II. Cleopatra and Antony.

The religion of ancient Rome;

"Works bearing on the early religion of Rome": p. [114]

History of Cleopatra, queen of Egypt.

Mode of access: Internet.

Geschichte des Pyrrhus, neu untersucht und nach den quellen dargestellt ...

Mode of access: Internet.

König Philipp, Sohn des Amyntas von Makedonien, und die hellenischen Staaten,

Mode of access: Internet.

Mithridate, tragédie,

Mode of access: Internet.

All for love : or, The world well lost : a tragedy, as it is acted at the Theatres-Royal in Drury-Lane and Covent-Garden /

About Antony and Cleopatra.

Analecta ad antiqvitates medicas : qvibus anatome Aegyptorvm et Hippocratis, nec non mortis genvs qvo Cleopatra regina periit explicantvr /

Includes bibliographical footnotes.

Herod and Mariamne.

Mode of access: Internet.

Demosthenes : the first Philippic /

Includes bibliographical references.

Three plays for Puritans: The devil's disciple; Cæsar and Cleopatra:

Mode of access: Internet.

Effect of cytochalasin B on 3-O-[(14)C]-methyl-D-glucose or D-[U-(14)C]glucose handling by BRIN-BD11 cells.

The present study aimed to investigate the effects of cytochalasin B (20 μM) on the uptake of 3-O-[(14)C]-methyl-D-glucose or D-[U-(14)C]glucose (8.3 mM each) by BRIN-BD11 cells. Taking into account the distribution space of tritiated water ((3)HOH), which was unexpectedly increased shortly after exposure of the cells to cytochalasin B and then progressively returned to its control values, and that of L-[1-(14)C]glucose, used as an extracellular marker, it was demonstrated that cytochalasin B caused a modest, but significant inhibition of the uptake of D-glucose and its non-metabolized analog by the BRIN-BD11 cells. These findings resemble those observed in acinar or ductal cells of the rat submaxillary gland and displayed a relative magnitude comparable to that found for the inhibition of D-glucose metabolism by cytochalasin B in purified pancreatic islet B cells. These findings reinforce the view that the primary site of action of cytochalasin B is located at the level of the plasma membrane.