Journal of molecular medicine : official organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
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Cystic fibrosis is caused by a defective expression of the cystic fibrosis transmembrane conductance regulator (Cftr) gene, which results in chronic pulmonary inflammation and infections. The pathophysiological mechanisms by which these changes are induced in the lungs of patients with cystic fibrosis require definition. This study found that Cftr deficiency in mice results in the upregulation and activation of CD95. ⋯ Genetic studies reveal that CD95 is crucially involved in the induction of aseptic inflammation, an increase in the bronchial cell death rate, and an increased susceptibility to infection of Cftr-deficient mice. All of these pathologies are partially corrected by heterozygosity of CD95 in Cftr-deficient mice. These findings identify CD95 as an important regulator of lung functions in cystic fibrosis and suggest that CD95 may be a novel target for treating cystic fibrosis.
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Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature characterized by constricted and remodeled pulmonary arteries. This phenomenon is associated with enhanced pulmonary artery smooth muscle cells proliferation and suppressed apoptosis, metabolism shift, inflammation, and several other features that are considered as hallmarks of cancer. Since oncogenes, tumor suppressors, and miRNAs are the major regulators of signaling in the cancer phenotype, we studied if the same type of regulation is operative in PAH. ⋯ Taken together, targeting oncoproteins or miRNAs appear as new therapeutic strategies for PAH. Several oncoprotein inhibitors are already in trials for cancer and could be soon available for PAH. Concerning miRNAs, the youth of this area makes therapies less achievable soon but not less interesting.
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Certain aminoglycosides are capable of inducing "translational readthrough" of premature termination codons (PTCs). However, toxicity and relative lack of efficacy deter treatment with clinically available aminoglycosides for genetic diseases caused by PTCs, including cystic fibrosis (CF). Using a structure-based approach, the novel aminoglycoside NB54 was developed that exhibits reduced toxicity and enhanced suppression of PTCs in cell-based reporter assays relative to gentamicin. ⋯ Systemic administration of NB54 to Cftr-/- mice expressing a human CFTR-G542X transgene restored 15-17% of the average stimulated transepithelial chloride currents observed in wild-type (Cftr+/+) mice, comparable to gentamicin. NB54 exhibited reduced cellular toxicity in vitro and was tolerated at higher concentrations than gentamicin in vivo. These results provide evidence that synthetic aminoglycosides are capable of PTC suppression in relevant human CF cells and a CF animal model and support further development of these compounds as a treatment modality for genetic diseases caused by PTCs.
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The hallucinogenic compound, salvinorin A, is a potent κ-opioid receptor (KOR) agonist. However, other target(s) than the KOR, such as the cannabinoid CB1 receptor, have been proposed to explain its multiple pharmacological actions. Here, we have evaluated the effect of salvinorin A in lipopolysaccharide (LPS)-stimulated macrophages as well as in models of inflammation in vivo. ⋯ The effect of salvinorin A on nitrite levels was reverted by the opioid antagonist naloxone, the KOR antagonist nor-binaltorphimine and by the CB1 antagonist rimonabant Salvinorin A also prevented KOR and CB1 hyperexpression induced by LPS. In vivo, salvinorin A reduced the LPS- and the carrageenan-induced paw oedema and formalin-induced inflammatory pain, in a nor-binaltorphimine and rimonabant-sensitive manner. It is concluded that salvinorin A-via KORs and CB1 receptors-exerts ultrapotent actions on macrophages and also shows moderate antinflammatory effects in vivo.
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Synaptic plasticity in the spinal cord and the cortex is believed to be important for the amplification of painful information in chronic pain conditions. The investigation of molecular mechanism responsible for maintaining injury-related plastic changes, such as through the study of long-term potentiation in these structures, provides potential novel targets for designing new medicine for chronic pain. Recent studies using integrative neurobiological approaches demonstrate that protein kinase M zeta (PKMζ) maintains pain-induced persistent changes in the anterior cingulate cortex (ACC), and inhibiting PKMζ by ζ-pseudosubstrate inhibitory peptide produces analgesic effects in animal models of chronic pain. We propose that targeting PKMζ, or its up- or downstream signaling proteins, in the ACC may provide novel clinical treatment for chronic pain.