Modulation of cellular circadian clocks by triterpenoids.

Many living organisms on earth have clock systems in their body. It has increasingly become clear that a disturbance in the internal clocks has negative effects on our body. Terpenes are organic compounds found in various plants that are reported to have several pharmacological actions. In this study, we focused on commercially available 27 triterpenoids and evaluated their influence on the circadian rhythm of human U2OS cells and mouse NIH3T3 cells. The expression level of Per2, one of the core clock genes, was measured using luminescent reporters over the time period of a few days. We found that 8 triterpenoids reset the phase of the circadian clocks. Representative compounds were corosolic acid, cucurbitacin B, and celastrol; similar effects were also confirmed with some structural analogues of cucurbitacin B and celastrol. These compounds shifted the phase bilaterally depending on the stimulus timing and also acted as synchronizers in desynchronized cells. The effective concentrations of cucurbitacin B and celastrol were less than 0.5 µM. In addition, cucurbitacin B and celastrol were also found to be effective in tissue explants in mice. Furthermore, celastrol dose-dependently shortened the period length of NIH3T3 cells. Some of these compounds are found in edible and medicinal plants and may help regulate our circadian clocks in everyday life.

Subacute Ingestion of Caffeine and Oolong Tea Increases Fat Oxidation without Affecting Energy Expenditure and Sleep Architecture: A Randomized, Placebo-Controlled, Double-Blinded Cross-Over Trial.

Ingesting oolong tea or caffeine acutely increases energy expenditure, and oolong tea, but not caffeine, stimulates fat oxidation. The acute effects of caffeine, such as increased heart rate and interference with sleep, diminish over 1-4 days, known as caffeine tolerance. During each 14-day session of the present study, 12 non-obese males consumed oolong tea (100 mg caffeine, 21.4 mg gallic acid, 97 mg catechins and 125 mg polymerized polyphenol), caffeine (100 mg), or placebo at breakfast and lunch. On day 14 of each session, 24-h indirect calorimetry and polysomnographic sleep recording were performed. Caffeine and oolong tea increased fat oxidation by ~20% without affecting energy expenditure over 24-h. The decrease in the respiratory quotient by oolong tea was greater than that by caffeine during sleep. The effect of oolong tea on fat oxidation was salient in the post-absorptive state. These findings suggest a role of unidentified ingredients in oolong tea to stimulate fat oxidation, and this effect is partially suppressed in a postprandial state. Two weeks of caffeine or oolong tea ingestion increased fat oxidation without interfering with sleep. The effects of subacute ingestion of caffeine and oolong tea differed from the acute effects, which is a particularly important consideration regarding habitual tea consumption.

A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer.

PURPOSE: Curcumin, a plant-derived natural polyphenol, could be a promising anti-cancer drug and shows synergic effects with cytotoxic agents. We evaluated the safety and feasibility of combination therapy using curcumin with gemcitabine-based chemotherapy. METHODS: Gemcitabine-resistant patients with pancreatic cancer received 8 g oral curcumin daily in combination with gemcitabine-based chemotherapy. The primary endpoint was safety for phase I and feasibility of oral curcumin for phase II study. RESULTS: Twenty-one patients were enrolled. No dose-limiting toxicities were observed in the phase I study and oral curcumin 8 g/day was selected as the recommended dose for the phase II study. No patients were withdrawn from this study because of the intolerability of curcumin, which met the primary endpoint of the phase II study, and the median compliance rate of oral curcumin was 100% (Range 79-100%). Median survival time after initiation of curcumin was 161 days (95% confidence interval 109-223 days) and 1-year survival rate was 19% (4.4-41.4%). Plasma curcumin levels ranged from 29 to 412 ng/ml in five patients tested. CONCLUSIONS: Combination therapy using 8 g oral curcumin daily with gemcitabine-based chemotherapy was safe and feasible in patients with pancreatic cancer and warrants further investigation into its efficacy.

Arterial spin-labeled MRI study of migraine attacks treated with rizatriptan.

Spin-tag perfusion imaging is an MRI method that quantitatively measures cerebral blood flow. Compared with conventional perfusion techniques, advantages of this arterial spin-labeling (ASL) include repeatability and the avoidance of intravenous contrast administration. In the present study, we performed an analysis of 3T high-field MRI examinations utilizing ASL perfusion during migraine attacks. A 32-year-old male patient was studied in three situations: during migraine attack within 1 h post-onset, 30 min after oral administration of rizatriptan 10 mg, and attack-free period. Normalized ASL images acquired during migraine attack showed significant relative hypoperfusion in the bilateral median thalamic areas including hypothalamus and significant relative hyperperfusion in the frontal cortex compared to images acquired during the migraine-free state. When normalized ASL images acquired 30 min after treatment were compared with those acquired during the attack, relative improvement of perfusion in the bilateral median thalamic areas including hypothalamus was observed. Hypothalamus and its surrounding areas may participate in the pathogenesis in migraine attack.