Jie Zhang

Zfp637 is a recently identified zinc finger protein, and its functions remain largely unknown. Here, we innovatively demonstrate the effects of Zfp637 on the differentiation of mouse spermatogonia and on its downstream target gene SOX2 in vitro. Obesity has been recognized as a chronic inflammatory disease that leads to decreased sexual function and sexual development disorders. We observed higher levels of IL-6 in serum and testis homogenates from obese mice compared with control mice. We also demonstrated that high levels of IL-6 inhibited Zfp637 expression, and we elucidated the underlying mechanisms. SOCS3 overexpression and STAT3 phosphorylation inhibitor (AG490) were used to investigate the function of the SOCS3/STAT3 pathway during this process. Our results showed that exposure of mouse spermatogonial cells to high levels of IL-6 inhibited Zfp637 expression by increasing SOCS3 expression and inhibiting the phosphorylation of STAT3, further reducing cellular differentiation. Consistent with the in vitro results, we observed increasing expression levels of SOCS3 and SOX2, but a reduction of Zfp637 expression, in obese mouse testes. In conclusion, Zfp637 plays a crucial role in spermatogenesis by downregulating SOX2 expression, and IL-6 can decrease the expression of Zfp637 through the SOCS3/STAT3 signaling pathway.

BACKGROUND: It is common clinical practice to administer reduced doses of opioid to patients suffering from hemorrhagic shock to minimize adverse hemodynamic consequences and to prevent prolonged opioid effect However, the scientific foundation supporting this practice is not well established. The aim of this study was to test the hypothesis that hemorrhagic shock alters both the distribution and clearance of opioids using fentanyl in a porcine isobaric hemorrhage model. METHODS: Eighteen pigs were randomized to shock or control groups. The animals in the shock group were subjected to hemorrhage using an isobaric method. Pigs in both groups received fentanyl (50 microg/kg) intravenously over 5 min. Frequent arterial blood samples were obtained for radioimmunoassay. Each animal's pharmacokinetic parameters were estimated by fitting a three-compartment model to the concentration versus time data Nonlinear mixed-effects population pharmacokinetic models examining the influence of mean arterial pressure and cardiac index were also constructed. Clinical simulations using the final population model were performed. RESULTS: The shock cohort reached substantially higher fentanyl concentrations. The shock group's central clearance and central- and second-compartment distribution volumes were significantly reduced. The most useful population model scaled all pharmacokinetic parameters to mean arterial pressure. The simulations illustrated that hemorrhagic shock results in higher fentanyl concentrations for any given dosage scheme. CONCLUSION: The essential finding of the study is that fentanyl pharmacokinetics are substantially altered by hemorrhagic shock. The reduced opioid requirement commonly observed during hemorrhagic shock is at least partially attributable to pharmacokinetic mechanisms.

This study evaluated the effect of locally applied heat on the transdermal delivery of testosterone. Six healthy adult volunteers were tested three times while receiving a 5 mg androgen patch, the same patch with a heat-generating patch, and no patch at all over 12 hours. Statistically significant differences in mean maximum serum testosterone concentration values were seen. Heat plus patch resulted in a mean maximum serum testosterone concentration of 939 ng/dl versus 635 ng/dl (patch only) and 425 ng/dl (no patch). (Heat + patch vs. no patch: p < 0.001; heat + patch vs. patch: p < 0.001; patch vs. no patch: p = 0.003.) The area under the curve of plasma testosterone concentration versus time values were means of 4114 ng/dl.h versus 1985 ng/dl.h for the patch-only group (p = 0.001). The use of heat improved absorption of transdermal testosterone and decreased time to peak serum testosterone concentrations, resulting in a statistically significant difference in mean maximum serum testosterone concentrations compared with the use of the patch without heat.