Our data show that enhanced oxidative stress and ER stress are major determinants of the strong apoptotic response elicited by the 19S DUB inhibitor b-AP15.

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Background: To investigate the effect of creatine and coenzyme Q10 (CoQ10) combination therapy on mild cognitive impairment (MCI) in Parkinson's disease (PD; PD-MCI) and its influences on plasma phospholipid (PL) levels in PD-MCI. Methods: The demographic data of 75 PD-MCI patients who enrolled in this collaborative PD study were collected. These patients were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) III and the Montreal Cognitive Assessment (MoCA). These 75 PD-MCI patients were randomly treated with creatine monohydrate 5 g b.i.d. and CoQ10 100 mg t.i.d. orally or placebo. MoCA evaluation and PL level measurements were performed after 12 and 18 months of treatment. Results: After 12 and 18 months of treatment, the differences in the MoCA scores of the combination therapy and control groups were statistically significant (p < 0.05 at 12 months and p < 0.01 at 18 months), and the plasma PL levels of the combination therapy group were significantly lower than those of the control group (p < 0.01 at 12 months and p < 0.001 at 18 months). Conclusions: Combination therapy with creatine and CoQ10 could delay the decline of cognitive function in PD-MCI patients and could lower their plasma PL levels; therefore, this combination therapy may have a neuroprotective function.

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Gossypol was considered a promising male contraceptive but finally failed due to two side effects: hypokalemia and the irreversibility of its contraceptive effect. Here we demonstrate that sustained zero-order release could be a solution for these problems. The in vitro release of gossypol from gossypol/PEG layer-by-layer films follows a perfect zero-order kinetics. In vivo tests indicate that the films can maintain the plasma drug concentration constant in male SD rats for ∼20 days for a 30-bilayer film. The plasma drug concentration is 2 orders of magnitude lower than the peak plasma drug concentration when administered orally and the daily dose is >50-fold lower than the commonly used contraceptive oral dose. However, significant antifertility effects were still observed. Furthermore, hypokalemia was not observed, and the antifertility effects can be reversed after a recovery period. The results suggest that zero-order release can significantly improve the desired antifertility effect of gossypol and, meanwhile, significantly reduce its side effects. We envision the drug could be developed to be an effective, safe, and reversible male contraceptive by zero-order release.

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