ß-Hydroxybutyric acid inhibits growth hormone-releasing hormone synthesis and secretion through the GPR109A/extracellular signal-regulated 1/2 signalling pathway in the hypothalamus.

ß-Hydroxybutyric acid (BHBA) has recently been shown to regulate hormone synthesis and secretion in the hypothalamus. However, little is known about the effects of BHBA-mediated hormone regulation or the detailed mechanisms by which BHBA regulates growth hormone-releasing hormone (GHRH) synthesis and secretion. In the present study, we examined the expression of the BHBA receptor GPR109A in primary hypothalamic cell cultures. We hypothesised that BHBA regulates GHRH via GPR109A and its downstream signals. Initial in vivo studies conducted in rats demonstrated that GHRH mRNA expression in the hypothalamus was strongly inversely correlated with BHBA levels in the cerebrospinal fluid during postnatal development (r = -0.89, P < 0.01). Furthermore, i.c.v. administration of BHBA acutely decreased GHRH mRNA expression in rats. Further in vitro studies revealed a decrease in GHRH synthesis and secretion in primary hypothalamic cells after treatment with BHBA; this effect was inhibited when hypothalamic cells were pretreated with pertussis toxin (PTX). BHBA had no effect on GHRH synthesis and secretion in GT1-7 cells, which do not exhibit cell surface expression of GPR109A. Furthermore, BHBA acutely decreased the transcription of the homeobox gene for Gsh-1 in the hypothalamus in both in vivo and in vitro, and this effect was also inhibited by PTX in vitro. In primary hypothalamic cells, BHBA activated the extracellular signal-regulated kinase (ERK)1/2, p38 and c-Jun N-terminal kinase mitogen-activated protein kinase (MAPK) kinases, as shown by western blot analysis. Moreover, inhibition of ERK1/2 with U0126 attenuated the BHBA-mediated reduction in Gsh-1 expression and GHRH synthesis and secretion. These results strongly suggest that BHBA directly regulates GHRH synthesis and secretion via the GPR109A/ERK1/2 MAPK pathway, and also that Gsh-1 is essential for this function.

Randomized clinical trial of Chinese herbal medications to reduce wound complications after mastectomy for breast carcinoma.

BACKGROUND: Ischaemia and necrosis of skin flaps is a common complication after mastectomy. This study evaluated the influence of anisodamine and Salvia miltiorrhiza on wound complications after mastectomy for breast cancer. METHODS: Ninety patients undergoing mastectomy for breast carcinoma were divided into three groups. Group 1 received routine wound care, group 2 received intravenous Salvia miltiorrhiza after surgery for 3 days and group 3 similarly received intravenous anisodamine. Skin flaps were observed on postoperative days 4 and 8; areas of wound ischaemia and necrosis were graded and adverse events recorded. RESULTS: There was no difference in demographic characteristics between the groups. At 4 days after surgery the rate of ischaemia and necrosis in groups 2 and 3 was significantly reduced compared with that in control group 1 (median wound score 6·80 versus 23·38, P = 0·002, and 3·76 versus 23·38, P < 0·001, respectively). This improvement in groups 2 and 3 continued to postoperative day 8 (both P < 0·001), but wound scores at this stage were better in group 3 than in group 2 (1·82 versus 6·92 respectively; P = 0·022). The volume of wound drainage was lower in group 3 than in group 1 (P = 0·004). The incidence of adverse effects was highest in group 3, and two patients in this group discontinued treatment. No significant complications were noted in group 2. CONCLUSION: Anisodamine and S. miltiorrhiza were both effective in reducing skin flap ischaemia and necrosis after mastectomy, although anisodamine was associated with a higher rate of adverse effects.

Electrospray ionization mass spectra of amino acid phosphoramidates of adenosine.

Amino acid phosphoramidates of adenosine were synthesized and determined by positive and negative ion electrospray ionization mass spectrometry (ESI-MS) in conjunction with tandem mass spectrometry (MS/MS). The fragmentation pathways were investigated. In the positive ion mass spectra abundant characteristic fragment ions appeared, and many complementary ions were found. In the negative ion mass spectra only a few fragment ions were observed, and most of them contained phosphoryl groups. The results show that ESI-MS is a useful tool for structural determination of amino acid phosphoramidates of nucleosides.