History-dependent perturbation response in limb muscle.

Muscle mediates movement but movement is typically unsteady and perturbed. Muscle is known to behave non-linearly and with history-dependent properties during steady locomotion, but the importance of history dependence in mediating muscle function during perturbations remains less clear. To explore the capacity of muscles to mitigate perturbations during locomotion, we constructed a series of perturbations that varied only in kinematic history, keeping instantaneous position, velocity and time from stimulation constant. We found that the response of muscle to a perturbation is profoundly history dependent, varying 4-fold as baseline frequency changes, and dissipating energy equivalent to ∼6 times the kinetic energy of all the limbs in 5 ms (nearly 2400 W kg-1). Muscle energy dissipation during a perturbation is predicted primarily by the force at the onset of the perturbation. This relationship holds across different frequencies and timings of stimulation. This history dependence behaves like a viscoelastic memory producing perturbation responses that vary with the frequency of the underlying movement.

Inhibition of Prostate Cancer Cells by 4,5-Dicaffeoylquinic Acid through Cell Cycle Arrest.

Prostate cancer is a major cause of cancer-related mortality in men. Even though current therapeutic management has contributed to reducing mortality, additional intervention strategies are warranted to further improve the outcomes. To this end, we have investigated the efficacy of dicaffeoylquinic acids, ingredients in Yerba Mate (Ilex paraguariensis), an evergreen cultivated in South America, the leaves of which are used to prepare a tea/coffee-like drink. Of the various analogs tested, 4,5-dicaffeoylquinic acid (4,5-diCQA) was the most active molecule against DU-145 prostate cancer cells with a 50% inhibitory concentration (IC50) of 5 µM. 4,5-diCQA was active both under normoxic and hypoxic conditions. The effect of 72-hour treatment on DU-145 cells persisted for an extended time period as assessed by clonogenic assay. Mechanistic studies revealed that the toxic effect was not due to induction of programmed cell death but through cell cycle arrest at S phase. Additionally, 4,5-diCQA did not impact PI3K/MAPK signaling pathway nor did it affect the depolarization of the mitochondrial membrane. 4,5-diCQA-induced accumulation of cells in the S-phase also seems to negatively impact Bcl-2 expression. 4,5-diCQA also exhibited inhibitory activity on LNCaP and PC-3 prostate cancer cells suggesting that it has therapeutic potential on a broad range of prostate cancers. Taken together, the novel inhibitory activity and mechanism of action of 4,5-diCQA opens up potential therapeutic options for using this molecule as monotherapy as well as in combinatorial therapies for the clinical management of prostate cancer.