Flavokawain B alleviates LPS-induced acute lung injury via targeting myeloid differentiation factor 2.

Acute lung injury (ALI) is a sudden onset systemic inflammatory response. ALI causes severe morbidity and death and currently no effective pharmacological therapies exist. Natural products represent an excellent resource for discovering new drugs. Screening anti-inflammatory compounds from the natural product bank may offer viable candidates for molecular-based therapies for ALI. In this study, 165 natural compounds were screened for anti-inflammatory activity in lipopolysaccharide (LPS)-challenged macrophages. Among the screened compounds, flavokawain B (FKB) significantly reduced LPS-induced pro-inflammatory IL-6 secretion in macrophages. FKB also reduced the formation of LPS/TLR4/MD2 complex by competitively binding to MD2, suppressing downstream MAPK and NF-κB signaling activation. Finally, FKB treatment of mice reduced LPS-induced lung injury, systemic and local inflammatory cytokine production, and macrophage infiltration in lungs. These protective activities manifested as increased survival in the ALI model, and reduced mortality upon bacterial infection. In summary, we demonstrate that the natural product FKB protects against LPS-induced lung injury and sepsis by interacting with MD2 and inhibiting inflammatory responses. FKB may potentially serve as a therapeutic option for the treatment of ALI.

A combination of models for end-stage liver disease and cirrhosis-related complications to predict the prognosis of liver cirrhosis.

BACKGROUND: The Child-Pugh score, the model for end-stage liver disease (MELD) score, and the occurrence of cirrhosis-related complications are independent prognostic predictors used in the assessment of chronic liver diseases. OBJECTIVES: The objectives of this study were to determine the best prognostic scoring system, and to create a combined method to predict the prognosis of liver cirrhosis more accurately. METHODS: We retrospectively reviewed 435 cirrhotic patients from January 2009 to June 2010 and evaluated their short- and medium-term survival. Child-Pugh, MELD and its advanced scoring systems were computed for each patient. The sensitivity and specificity of these scoring systems were analyzed and their validity was assessed using concordance (c)-statistics in predicting the prognosis of cirrhotic patients. RESULTS: Overall, 107 patients died within 6 months and 150 patients died within 1 year. The clinical and biochemical characteristics, cirrhosis-related complications, and the scores were significantly different among the survivors and patients who died. The largest area under the receiver operating characteristic curve was 0.741 for the integrated MELD (iMELD) at 6 months and 0.713 for iMELD at 12 months, indicating that iMELD was the best scoring system tested. Given this result, we created a new scoring system that combined iMELD and an index of cirrhosis-related complications, called iMELD-C. This novel system had c indexes of 0.758 for the 6-month survival and 0.746 for the 1-year survival. CONCLUSIONS: The iMELD-C score is a better predictor of both short- and medium-term survival in patients with cirrhosis.