ABSTRACT
Gender differences in fatigue manifest as females being more prone to feel exhaustion and having lower muscle endurance. However, the mechanisms of these effects remain unclear. We investigated whether orosomucoid, an endogenous anti-fatigue protein that enhances muscle endurance, is involved in this regulation. Female rats exhibited lower muscle endurance, and this gender difference disappeared in orosomucoid-1-deficient mice. Female rats also exhibited weaker orosomucoid induction in serum, liver and muscle in response to fatigue compared with male rats. Ovariectomy elevated orosomucoid levels and increased swimming time, and estrogen replenishment reversed these effects. Exogenous estrogen treatment in male and female mice produced opposite effects. Estrogen decreased orosomucoid expression and its promoter activity in C2C12 muscle and Chang liver cells in vitro, and estrogen receptor or p38 mitogen-activated protein kinase blockade abolished this effect. Therefore, estrogen negatively regulates orosomucoid expression that is responsible for the weaker muscle endurance in females.
ABSTRACT
OBJECTIVE Although it is generally believed that nicotine accounts for the beneficial effect of smoking on ulcerative colitis, the underlying mechanisms remain not well understood. Our previous finding that nicotine inhibits inflammatory responses through inducing miRNA-124 prompted us to ask whether the miRNA is involved in the protective action of nicotine on UC. METHODS MiR-124 expres-sion in colon tissues and cells was determined by q-PCR and in situ hybridization.The effect of miR-124 on protective role of nicotine in ulcerative colitis was evaluated in DSS-treated mice and IL-6-treated Caco-2 colon epithelial cells. Expression of p-STAT3/STAT3 was detected by immunohistochemistry and Western-blot analysis. RESULTS miR-124 expression is upregulated in colon tissues from UC patients and DSS-induced colitis mice. Nicotine treatment further elevated miR-124 level in lympho-cytes isolated from human ulcerative colonic mucosa and ulcerative colon tissues from DSS mice,both in infiltrated lymphocytes and epithelial cells. Administration of nicotine also reduced weight loss, improved DAI and decreased HE score in DSS-induced colitis mice.Moreover,knockdown of miR-124 in vivo significantly diminished the beneficial effect of nicotine on murine colitis, and in vitro on IL-6-treated Caco-2 colon epithelial cells.Further analysis indicated that nicotine inhibited STAT3 activation in vivo and in IL-6-treated Caco-2 colon epithelial cells and Jurkat human T lymphocytes,in which miR-124 knockdown led to increased activation of STAT3. Blocking STAT3 activity alone is beneficial for DSS colitis and also abolished nicotine′s protective effect in this model.CONCLUSION These data indicated that nicotine exerts its protective action in UC through inducing miR-124 and its effect on STAT3, and suggest that the miR-124/STAT3 system is a potential target for the therapeutic intervention of UC.
ABSTRACT
Despite of tremendous progresses made in the genomics, stem cell technology, and microelectronics, challenges remain for the diagnosis and treatment of many diseases including cancer. Thus the conception of "translational medicine" appeared and it is generally believed that translational researches should be intensified. Translational researches not only include the application of new methods and advanced technologies, but also emphasize the raise of problems from clinical practice and study and solve them for diagnosis and treatment. Another important aspect of translational medicine is personalized treatment of diseases, i.e., using targeted drugs against specific molecular changes in individual patient. Although there are only a handful of examples for targeted therapy, we believe that, with the deeper understanding of the mechanisms of more diseases, discovery of more biomarkers and diagnostic methods, and development of more targeted drugs, personalized therapy will become popular in clinic in the future.