The traditional Chinese medical compound Rocaglamide protects nonmalignant primary cells from DNA damage-induced toxicity by inhibition of p53 expression.

One of the main obstacles of conventional anticancer therapy is the toxicity of chemotherapeutics to normal tissues. So far, clinical approaches that aim to specifically reduce chemotherapy-mediated toxicities are rare. Recently, a number of studies have demonstrated that herbal extracts derived from traditional Chinese medicine (TCM) may reduce chemotherapy-induced side effects. Thus, we screened a panel of published cancer-inhibiting TCM compounds for their chemoprotective potential and identified the phytochemical Rocaglamide (Roc-A) as a candidate. We show that Roc-A significantly reduces apoptotic cell death induced by DNA-damaging anticancer drugs in primary human and murine cells. Investigation of the molecular mechanism of Roc-A-mediated protection revealed that Roc-A specifically blocks DNA damage-induced upregulation of the transcription factor p53 by inhibiting its protein synthesis. The essential role of p53 in Roc-A-mediated protection was confirmed by siRNA knockdown of p53 and by comparison of the effects of Roc-A on chemoprotection of splenocytes isolated from wild-type and p53-deficient mice. Importantly, Roc-A did not protect p53-deficient or -mutated cancer cells. Our data suggest that Roc-A may be used as an adjuvant to reduce the side effects of chemotherapy in patients with p53-deficient or -mutated tumors.

TNF-α mediates mitochondrial uncoupling and enhances ROS-dependent cell migration via NF-κB activation in liver cells.

Development of hepatocellular carcinoma (HCC) is accompanied by a continuous increase in reactive oxygen species (ROS) levels. To investigate the primary source of ROS in liver cells, we used tumor necrosis factor-alpha (TNF-α) as stimulus. Applying inhibitors against the respiratory chain complexes, we identified mitochondria as primary source of ROS production. TNF-α altered mitochondrial integrity by mimicking a mild uncoupling effect in liver cells, as indicated by a 40% reduction in membrane potential and ATP depletion (35%). TNF-α-induced ROS production activated NF-κB 3.5-fold and subsequently enhanced migration up to 12.7-fold. This study identifies complex I and complex III of the mitochondrial respiratory chain as point of release of ROS upon TNF-α stimulation of liver cells, which enhances cell migration by activating NF-κB signalling.

Conserving large populations of lions - the argument for fences has holes.

Packer et al. reported that fenced lion populations attain densities closer to carrying capacity than unfenced populations. However, fenced populations are often maintained above carrying capacity, and most are small. Many more lions are conserved per dollar invested in unfenced ecosystems, which avoid the ecological and economic costs of fencing.

Primary total knee arthroplasty in stiff and ankylosed knees.

This study reviewed 71 patients who underwent 82 total knee arthroplasties between 1974 and 1987. All patients had severe limitations of motion preoperatively with a total preoperative arc of motion of < or = 50 degrees. Follow-up ranged from 2 to 12 years (average: 5.3 years). The average preoperative knee score was 38 (range: 14 to 54). The average preoperative arc of motion was 36 degrees (range: 0 degree to 50 degrees), with an average flexion contracture of 22 degrees average maximum flexion of 58 degrees. Postoperatively, the average knee score was 80 (range: 0 to 98). The average postoperative arc of motion was 93 degrees (range: 35 degrees to 130 degrees), with an average maximum flexion of 94 degrees. Nine knees had 5 degrees flexion contractures, while 5 knees had 10 degrees flexion contractures. Postoperatively, no knee had a flexion contracture > 10 degrees. Two knees had a decreased range of motion postoperatively. Two knees with severe flexion-valgus deformities developed peroneal nerve palsies that both resolved. Total knee arthroplasty in stiff or ankylosed knees can produce good or excellent results and can lead to significant improvement in range of motion and pain.