25793180
Sepsis induces the transcription of the glucocorticoid receptor in skeletal muscle cells.
Evidence from a recent study indicates that glucocorticoids (GCs) mediate skeletal muscle proteolysis during sepsis via the GC receptor (GR) pathway. Attempts to identify the mechanisms regulating GR gene expression in skeletal muscle during sepsis have been hampered by the lack of an appropriate in vitro model system that can mimic in vivo septic conditions. In the present study, we report that GR gene transcription in L6 myocytes in vitro is up-regulated by treatment with sera from septic rats in a manner similar to that measured in septic rats in vivo. Sera from septic rats were collected from animals in which sepsis was induced by caecal ligation and puncture and from control rats that were sham-operated. Finally, by treating L6 myotubes with the GR antagonist RU 38486, thereby preventing sepsis-induced GR transcription, we confirmed that the possible septic effect on the GR was due to increased GCs. L6 myocytes treated with sera from septic rats might therefore be useful as an experimental model for identifying the molecular mechanisms by which the GR regulates muscle cachexia during sepsis. Furthermore, RU 38486 inhibited the sepsis-induced increase in total and myofibrillar energy-dependent protein breakdown rates in incubated extensor digitorum longus muscles from septic and sham-operated rats, as measured by release of tyrosine and 3-methylhistidine respectively. Our results demonstrate for the first time that sepsis induces GR transcription in skeletal muscle, and supports the hypothesis that the GC-induced proteolysis under sepsis is partially a consequence of GR activation.
36944421
Effect of burn injury on glucocorticoid receptor binding activity in rat muscle.
Burn injury is associated with increased muscle proteolysis and up-regulated gene expression in the proteolytic pathway. Glucocorticoids (GCs) are the most important mediator of burn injury induced muscle cachexia. However, the understanding of the mechanisms of GCs action in response to burn injury remains elusive. It is well known that GC acts by binding its own receptor. Therefore, in the present study, we examined the influence of burn injury on the hormone binding activity of the glucocorticoid receptor (GR) in skeletal muscle. Burn injury resulted in increased hormone binding activity in extensor digitorum longus (EDL) and soleus muscles. Scatchard plots revealed that the increased GR hormone binding activity reflected increased numbers of hormone binding sites, whereas receptor affinity for GCs was unchanged. Western blot analysis showed that dissociation of GR/heat shock protein 90 heterocomplex or increase in GR protein may account for the effect of burn injury. The GR antagonist RU 38486 blocked the burn injury-induced increase in GR hormone binding activity, implicating a positive regulatory effect of GCs on GR binding activity under the present experimental conditions.
41739708
Influence of N-substituent and solvent on internal conversion in 1-aminonaphthalenes.
N-Methyl-N-methoxycarbonylmethyl-1-aminonaphthalene (MMAN) and N,N-dimethoxycarbonylmethyl-1-aminonaphthalene (DCAN) were synthesized and their fluorescence and absorption spectra in solvents of varied polarity were investigated and compared to those of 1-dimethylaminonaphthylene (DMAN). The data were discussed in terms of the N-substitution effects on the internal conversion (IC). Results showed that the IC was enhanced when the N-methyl group in DMAN was replaced by N-CH2CO2CH3.
902426
The effect of telomerase activity on vascular smooth muscle cell proliferation in type 2 diabetes in vivo and in vitro.
Serious complications as a result of type 2 diabetes mellitus (T2DM) are becoming a major health concern. In the present study, it was hypothesized that telomerase activity is upregulated in vascular smooth muscle cells (VSMCs) during proliferation in T2DM and that the application of telomerase inhibitors impedes the proliferation of VSMCs in vitro. Male Wistar rats were randomly allocated into the normal control (NC) or diabetic (DM) group. Diabetes was induced by high‑fat feeding and a low dose of streptozotocin (STZ; 30 mg/kg). Primary VSMC cultures were exposed to normal (5.5 mM) or high (25 mM) glucose and insulin (100 nM) in the presence and absence of various concentrations of antisense oligoribonucleotides (ASODNs) for varying lengths of time. Telomerase activity and the proliferation of VSMCs were measured. Results showed that there was a significant increase in the levels of fasting glucose, insulin, triglycerides (TG) and free fatty acids (FFAs) in the diabetic group. Telomerase activity and the proliferation of VSMCs were significantly higher in the diabetic group in vivo and in the high glucose and insulin (HGI)-treated group in vitro (P<0.01). ASODNs significantly inhibited the proliferation of VSMCs in a concentration- and time‑dependent manner (P<0.01). In conclusion, hyperglycemia and hyperinsulinemia stimulate telomerase activity and the proliferation of VSMCs, while the inhibition of telomerase activity reduces the proliferation of VSMCs, indicating that telomerase may be involved in the pathological process of diabetic vascular disease.
5630256
Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas
The von Hippel–Lindau tumor suppressor protein (pVHL) suppresses tumor formation by binding the α subunits of hypoxia-inducible-factors responsible for stimulating tumor angiogenesis and glycolysis, and targeting them for ubiquitination and proteasomal destruction. Loss of pVHL leads to tumorigenesis and development of sporadic renal cell carcinomas and central nervous system hemangioblastomas. In the present study, we investigated whether engineered overexpression of pVHL in C6 glioma cells, which already express endogenous pVHL, would suppress the tumorigenicity of this particular tumor cell type. C6 cells overexpressing VHL displayed a reduced growth rate (70% inhibition) compared to the parental cell line when subcutaneously implanted in athymic (nu/nu) mice. Growth inhibition was associated with a 50% reduction in the number of tumor vessels and a 60% increase in tumor cell apoptosis, due in part to downregulation of HIF-1, VEGF, and the antiapoptotic factor Bcl-2, respectively. Gene transfer of VHL suppressed the growth of established C6 gliomas, and synergized with antisense HIF-1 to completely eradicate tumors. The data suggest that VHL gene therapy and/or agents that increase VHL expression could have utility in the treatment of gliomas, particularly when combined with agents that inhibit the expression or function of HIF-1.
7754587
Effect of conventional interferon-α in patients with HBeAg-positive chronic hepatitis B: a systematic review and meta-analysis.
BACKGROUND
Although a few studies have tested the effect of interferon-α on chronic hepatitis B, its treatment effect remains uncertain, and the association of treatment effect with intervention characteristics has not been thoroughly explored. This study examined the effect of IFN-α in patients with HBeAg-positive chronic hepatitis B, and investigated the characteristics associated with treatment effect.


METHODS
We searched MEDLINE, Scientific Citation Index, Current Content Connect, Cochrane Controlled Trial Register, and Chinese Biomedical Database, all up to 15 September 2009. We included randomized trials comparing IFN-α to placebo, no treatment, or standard care (SC) in patients with HBeAg-positive chronic hepatitis B. Two reviewers assessed the risk of bias and extracted data, independently and in duplicate. We conducted meta-analyses of the included studies, and subgroup analyses to examine the association of pre-specified characteristics (eg, dose, treatment duration) with treatment effect.


RESULTS
A total of 31 randomized controlled trials, involving 2164 patients, were included. The risk of bias varied across studies. Compared with placebo, no treatment, or SC, IFN-α improved loss of HBeAg (OR 2.36, 95% CI 1.83 to 3.04), HBV DNA undetectability (OR 2.04, 95% CI 1.28 to 3.32), HBeAg seroconversion (OR 1.82, 95% CI 1.26 to 2.62), ALT normalization (OR 1.24, 95% CI 1.01 to 1.56), and loss of HBsAg (OR 2.45, 95% CI 1.22 to 4.91). Treatment effects differed in high versus low dose, and long versus short duration of IFN-α. The effect of high dose IFN-α (OR 3.28, 95% CI 2.31 to 4.66) is statistically larger than that of low dose IFN-α (OR 1.58, 95% CI 1.10 to 2.28) on loss of HBeAg (interaction P = 0.017), and longer IFN-α treatment durations produce greater effects (OR 3.28, 95% CI 2.16 to 5.00) than do shorter durations (OR 1.94, 95% CI 0.42 to 2.66, interaction P = 0.038). High dose IFN-α had a significant effect on HBV DNA undetectability (OR 2.80, 95% CI 2.03 to 3.86), while low dose IFN-α did not (OR 0.93, 95% CI 0.61 to 1.41, interaction P = 0.01); longer treatments significantly improved HBV DNA undetectability (OR 2.58, 95% CI 1.62 to 4.12), but shorter durations did not (OR 1.28, 95% CI 0.83 to 1.97, interaction P = 0.024).


CONCLUSIONS
IFN-α can improve serological, biomedical, and virological response. Higher doses and prolonged treatments appear to have larger treatment benefits than lower doses and shorter treatments. However, the increased adverse reactions and costs associated with higher doses and prolonged treatment warrant caution in applying these results.
2844047
Prescribing behaviour of village doctors under China's New Cooperative Medical Scheme.
In 2003, China introduced a new community-based rural health insurance called the New Cooperative Medical Scheme (NCMS). In 2005, to assess the NCMS effects on village doctors' prescribing behaviour, we compared an NCMS county and a non-NCMS county in Shandong Province. We collected information from a representative total of 2271 patient visits in 30 village health stations (15 per county). The average number of drugs prescribed (4.6 in the NCMS county vs. 3.1 in the non-NCMS county) and use of antibiotics (72.4% vs. 59.3%) and injections (65.1% vs. 56.3%) were high in both counties, and higher in the NCMS county. Within NCMS villages, prescribing for insured vs. uninsured patients showed a similar pattern with more drugs, antibiotics and injections for those insured. Overall, for NCMS patients, the prescription excess was about equal in value to their 20% fee discount. We conclude that over-prescribing is common in villages and worse with NCMS health insurance, raising concerns for health service quality and drug-use safety. We propose that the NCMS should be redesigned with incentives for service quality improvement. A stricter regulatory environment for doctors' prescriptions is needed in rural China to counter irrational drug use.