Effects of a Caspase and a Calpain Inhibitor on Resting Energy Expenditures in Normal and Hypermetabolic Rats: a Pilot Study

Several diseases induce hypermetabolism, which is characterized by increases in resting energy expenditures (REE) and whole body protein loss. Exaggerated protein degradation is thought to be the driving force underlying this response. The effects of caspase and calpain inhibitors on REE in physiological and hypermetabolic conditions, however, are unknown. Thus, we studied whether MDL28170 (calpain inhibitor) or z-VAD-fmk (caspase inhibitor) affect REE under physiological conditions and during hypermetabolism post-burn. Rats were treated five times weekly and observed for 6 weeks. Treatment was started 2 h (early) or 48 h (late) after burn. In normal rats, MDL28170 transiently increased REE to 130 % of normal during week 2-4. z-VAD-fmk reduced REE by 20-25 % throughout the observation period. Within 14 days after burns, REE increased to 130±5 %. Whereas MDL28170/early treatment did not affect REE, MDL28170/late transiently increased REE to 180±10 % of normal by week 4 post-burn. In contrast, with z-VAD-fmk/early REE remained between 90-110 % of normal post-burn. z-VAD-fmk/late did not affect burn-induced increases in REE. These data suggest that caspase cascades contribute to the development of hypermetabolism and that burn-induced hypermetabolism can be pharmacologically modulated. Our data point towards caspase cascades as possible therapeutic targets to attenuate hypermetabolism after burns, and possibly in other catabolic disease processes.

Active Constituents fromLiriope platyphyllaRoot against Cancer GrowthIn Vitro

Liriope spicatais a well-known herb in traditional Chinese medicine, and its root has been clinically demonstrated to be effective in the treatment of metabolic and neural disorders. The constituents isolated fromLiriopehave also recently been shown to possess anticancer activity, although the mechanism of which remains largely unknown. Here, we illustrate the anticancer activity of LPRP-9, one of the active fractions we fractionated from theLiriope platyphyllaroot part (LPRP) extract. Treatment with LPRP-9 significantly inhibited proliferation of cancer cell lines MCF-7 and Huh-7 and down-regulated the phosphorylation of AKT. LPRP-9 also activates the stress-activated MPAK, JNK, p38 pathways, the p53 cell-cycle checkpoint pathway, and a series of caspase cascades while downregulating expression of antiapoptotic factors Bcl-2, Bcl-XL, and survivin. Such activities strongly suggest a role for LPRP-9 in apoptosis and autophagy. We further purified and identified the compound (−)-Liriopein B from LPRP-9, which is capable of inhibiting AKT phosphorylation at low concentration. The overall result highlights the anticancer property of LPRP-9, suggests its mechanism for inhibition of proliferation and promotion of cell death for cancer cells via regulation of multitarget pathways, and denotes the importance of purifying components of fraction LPRP-9 to aid cancer therapy.