The Sirt1 activator resveratrol improved hematopoiesis in pancytopenia mice induced by irradiation.

Bone marrow failure is a disease syndrome with the disability to produce mature blood cells. Pancytopenia is the most common manifestation of bone marrow failure. Sirt1 is important for the function of hematopoietic stem cells, we hypothesized that Sirt1 activation may improve hematopoiesis. The Sirt1 heterozygous and wild type mice were exposed to lethal 6.5 Gy 60Co-γ rays. The survival time and hematopoietic indexes were evaluated. The survival time of Sirt1 deficiency mice was significantly decreased. The numbers of platelets (PLT), reticulocytes (RET) and white blood cells (WBC) were significantly decreased. C57BL/6 mice were exposed to 6.5 Gy 60Co-γ rays then administrated with resveratrol (20 mg/kg/d) or vehicle. Resveratrol increased the survival time and protective against irradiation induced hematopoietic damage. Resveratrol also significantly increased the numbers of PLT, RET and WBC of mice. It also increased the hematopoietic area and karyocytes number. In HEK293T cells, the expression of LKB1 was significantly increased in cytoplasm but not in nuclei when treated with resveratrol (50 µM). These results suggest that Sirt1 deficiency might aggravate bone marrow failure. Resveratrol corrected this hematopoietic defect and LKB1 might involve in the protective effect on bone marrow failure.

The Combination of Scopolamine and Psychostimulants for the Prevention of Severe Motion Sickness.

BACKGROUND AND AIMS: Severe motion sickness is a huge obstacle for people conducting precise aviation, marine or emergency service tasks. The combination of scopolamine and d-amphetamine is most effective in preventing severe motion sickness. However, this combination is not included in any present pharmacopoeia due to the abuse liability of d-amphetamine. We wanted to find a combination to replace it for the treatment of severe motion sickness. METHODS AND RESULTS: We compared the efficacy of scopolamine, diphenhydramine, and granisetron (representing three classes of drugs) with different doses, and found that scopolamine was the most effective one. We also found scopolamine inhibited central nervous system at therapeutic doses and caused anxiety. Then, we combined it with different doses of psychostimulants (d-amphetamine, modafinil, caffeine) to find the best combination for motion sickness. The efficacy of scopolamine with modafinil (1 + 10 mg/kg) was equivalent to that of scopolamine with d-amphetamine (1 + 1 mg/kg); This combination also excited central nervous system and abolished the anxiety caused by scopolamine. CONCLUSIONS: The optimal dose ratio of scopolamine and modafinil is 1:10. This combination is beneficial for motion sickness and can abolish the side effects of scopolamine. So, it might be a good replacement of scopolamine and d-amphetamine for severe motion sickness.

ALDH2 protects against stroke by clearing 4-HNE.

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that metabolizes ethanol and toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE). Using an unbiased proteomic search, we identified ALDH2 deficiency in stroke-prone spontaneously hypertensive rats (SHR-SP) as compared with spontaneously hypertensive rats (SHR). We concluded the causative role of ALDH2 deficiency in neuronal injury as overexpression or activation of ALDH2 conferred neuroprotection by clearing 4-HNE in in vitro studies. Further, ALDH2-knockdown rats revealed the absence of neuroprotective effects of PKCε. Moderate ethanol administration that is known to exert protection against stroke was shown to enhance the detoxification of 4-HNE, and to protect against ischemic cerebral injury through the PKCε-ALDH2 pathway. In SHR-SP, serum 4-HNE level was persistently elevated and correlated inversely with the lifespan. The role of 4-HNE in stroke in humans was also suggested by persistent elevation of its plasma levels for at least 6 months after stroke. Lastly, we observed that 21 of 1 242 subjects followed for 8 years who developed stroke had higher initial plasma 4-HNE levels than those who did not develop stroke. These findings suggest that activation of the ALDH2 pathway may serve as a useful index in the identification of stroke-prone subjects, and the ALDH2 pathway may be a potential target of therapeutic intervention in stroke.