Inhibition of osteoclast differentiation and bone resorption by rotenone, through down-regulation of RANKL-induced c-Fos and NFATc1 expression.

Osteoclasts are responsible for bone erosion in diseases as diverse as osteoporosis, periodontitis, and rheumatoid arthritis. Natural plant-derived products have received recent attention as potential therapeutic and preventative drugs in human disease. The effect of rotenone in RANKL-induced osteoclast differentiation was examined in this study. Rotenone inhibited RANKL-mediated osteoclast differentiation in bone marrow macrophages (BMMs) in a dose-dependent manner without any evidence of cytotoxicity. The mRNA expression of c-Fos, NFATc1, TRAP, and OSCAR in RANKL-treated BMMs was inhibited by rotenone treatment. Rotenone strongly inhibited p38 and ERK phosphorylation and I-kappaB degradation in RANKL-stimulated BMMs, and did not inhibit JNK phosphorylation. Further, RANKL-induced c-Fos and NFATc1 protein expression was suppressed by rotenone. Rotenone additionally inhibited the bone resorptive activity of differentiated osteoclasts. A lipopolysaccharide (LPS)-induced bone erosion study was also performed to assess the effects of rotenone in vivo. Mice treated with rotenone demonstrated marked attenuation of bone erosion based on Micro CT and histologic analysis of femurs. These results collectively suggested that rotenone demonstrated inhibitory effects on osteoclast differentiation in vitro and suppressed inflammatory bone loss in vivo. Rotenone may therefore serve as a useful drug in the prevention of bone loss.

Isolated smoke inhalation injuries: acute respiratory dysfunction, clinical outcomes, and short-term evolution of pulmonary functions with the effects of steroids.

Relatively few reports exist regarding isolated smoke inhalation injuries in human patients. In this study, we describe the acute manifestations and short-term evolution of respiratory injuries after isolated smoke inhalation in victims of fires. Ninety-six patients admitted as the result of a subway fire were examined for acute respiratory dysfunction with clinical outcomes. Some of the survivors suffering from less severe injuries were evaluated for changes in pulmonary function over time, with the effects of steroid treatment. In 13 patients (14%), immediate respiratory failure resulted from ventilatory insufficiency, which was induced principally by mechanical airway obstruction, and manifested as significantly lowered pH and higher PaCO2 levels than in the patients requiring no mechanical ventilation. Toilet bronchoscopy allowed for early liberation from mechanical ventilation. Along with the death of 4 patients (4%), vocal cord and tracheal stenosis were noted in 5 patients and 1 patient, respectively, among 17 patients for whom endotracheal intubation was required. Pulmonary functions improved significantly after 3 months, with no further changes being observed within the subsequent 3 months. Steroid therapy resulted in no additional improvements in the pulmonary functions of these patients. In patients with isolated smoke inhalation injuries, immediate ventilatory insufficiency resulting from mechanical airway obstruction should be watched for, and managed via toilet bronchoscopy. Vigilance is required to avoid airway complications after endotracheal intubation. The improvement of pulmonary functions progressed primarily within the first 3 months, whereas short-course steroid therapy exerted no influence on the eventual recovery of pulmonary functions in the less severe cases.