类阿片肽(Opioid peptides)的镇痛作用机制

改变吗啡骨架合成麻醉性镇痛药的报道已很多,就其结构活性研究成果发现,具天然吗啡相同的R~((-))这一立体特异性,确认了它们有强力的镇痛活性.麻醉性镇痛药设想有特异结合能的阿片受体,1973年已被实验证实脑内存在。但其分布不均一,在调节痛觉深部的脊髓后角,兰斑核,三叉神经下行核的罗氏胶质区、中脑导水管周围灰质等高密度地存在阿片受体。有关阿片受体的内在性活性物质,已从一组含多肽哺乳动物的脑、下垂体分离出两种脑啡肽(蛋-脑啡肽和亮-脑啡肽)及β-内啡肽的单体.从类阿片肽的发现推测可能存在调节内在性疼痛的机能.

Increased nociceptin/orphanin FQ plasma levels in hepatocellular carcinoma

AIM:The heptadecapeptide nociceptin alias orphanin FQ is the endogenous agonist of opioid receptor-likel receptor. It is involved in modulation of pain and cognition.High blood level was reported in patients with acute and chronic pain, and in Wilson disease.An accidental observation led us to investigate nociceptin in hepatocellular carcinoma. METHODS:Plasma nociceptin level was measured by radioimmunoassay,aprotinin was used as protease inhibitor. Hepatocellular carcinoma was diagnosed by laboratory, ultrasound,other imaging,and confirmed by fine needle biopsy.Results were compared to healthy controls and patients with other chronic liver diseases. RESULTS:Although nociceptin levels were elevated in patients with Wilson disease (14.0±2.7 pg/mL,n=26), primary biliary cirrhosis (12.1±3.2 pg/mL,n=21) and liver cirrhosis (12.8±4.0 pg/mL,n=15) compared to the healthy controls (9.2±1.8 pg/mL,n=29, P<0.001 for each),in patients with hepatocellular carcinoma a ten-fold increase was found (105.9±14.4 pg/mL,n=29,P<0.0001).High plasma levels were found in each hepatocellular carcinoma patient including those with normal alpha fetoprotein and those with pain (104.9±14.9 pg/mL,n=12) and without (107.7±14.5 pg/mL,n=6). CONCLUSION:A very high nociceptin plasma level seems to be an indicator for hepatocellular carcinoma.Further research is needed to clarify the mechanism and clinical significance of this novel finding.

Beta-endorphin in serum and seminal plasma in infertile men

Aim： To access beta-endorphin levels in serum as well as seminal plasma in different infertile male groups. Methods： Beta-endorphin was estimated in the serum and seminal plasma by enzyme-linked immunosorbent assay （ELISA） method in 80 infertile men equally divided into four groups： non-obstructive azoospermia （NOA）, obstructive azoospermia （OA）, congenital bilateral absent vas deferens （CBVAD） and asthenozoospermia. The results were compared to those of 20 normozoospermic proven fertile men. Results： There was a decrease in the mean levels of betaendorphin in the seminal plasma of all successive infertile groups （mean ± SD： NOA 51.30 ± 27.37, OA 51.88 ± 9.47, CBAVD 20.36 ± 13.39, asthenozoospermia 49.26 ± 12.49 pg/mL, respectively） compared to the normozoospermic fertile control （87.23 ± 29.55 pg/mL）. This relation was not present in mean serum level of beta-endorphin between four infertile groups （51.09 ± 14.71, 49.76 ± 12.4, 33.96 ± 7.2, 69.1 ± 16.57 pg/mL, respectively） and the fertile control group （49.26 ± 31.32 pg/mL）. The CBVAD group showed the lowest seminal plasma mean level of beta-endorphin. Testicular contribution of seminal beta-endorphin was estimated to be approximately 40%. Seminal beta-endorphin showed significant correlation with the sperm concentration （r = 0.699, P = 0.0188） and nonsignificant correlation with its serum level （r = 0.375, P = 0.185） or with the sperm motility percentage （r = 0.470, P = 0.899）. Conclusion： The estimation of beta-endorphin alone is not conclusive to evaluate male reproduction as there are many other opiates acting at the hypothalamic pituitary gonadal axis.

Rising plasma nociceptin level during development of HCC:A case report

AIM:Although liver cirrhosis is a predisposing factor for hepatocellular carcinoma (HCC),relatively few reports are available on HCC in primary biliary cirrhosis.High plasma nociceptin (N/OFQ) level has been shown in Wilson disease and in patients with acute and chronic pain. METHODS:We report a follow-up case of HCC,which developed in a patient with primary biliary cirrhosis.The tumor appeared 18 years after the diagnosis of PBC and led to death within two years.Alfa fetoprotein and serum nociceptin levels were monitored before and during the development of HCC. Nociceptin content was also measured in the tumor tissue. RESULTS:The importance and the curiosity of the presented case was the novel finding of the progressive elevation of plasma nociceptin level up to 17-fold (172 pg/mL) above the baseline (9.2±1.8 pg/mL),parallel with the elevation of alpha fetoprotein (from 13 ng/mL up to 3 480 ng/mL) during tumor development.Nociceptin content was more than 15-fold higher in the neoplastic tissue (0.16 pg/mg) than that in the tumor- free liver tissue samples (0.01 pg/mg) taken during the autopsy. CONCLUSION:Results are in concordance with our previous observation that a very high plasma nociceptin level may be considered as an indicator for hepatocellular carcinoma.

Characteristic fragmentation behavior of the analogs of endomorphin-2 with phenylglycine in position 3 or 4 by ESI-FT tandem mass spectrometry

A series of analogs of endomorphin-2 （EM-2） with phenylglycine （Phg） in position 3 or 4 were synthesized. In electrospray ionization Fourier transform ion cyclotron resonance （ESI-Fr-ICR） MS/MS spectra of these compounds, some b, y, a, and internal ions were observed and slight mass differences between the calculated and observed results are obtained. Their sequences were derived successfully. However, the MS/MS patterns of these analogs with Dphg and Lphg were very similar. It is hard to distinguish them by MS/MS spectra. Moreover, if the third position was substituted by phenylglycine （L or D）, a rearrangement could occur in MS/MS experiment to lose proline residue.

Enzymatic clickable functionalization of peptides via computationally engineered peptide amidase

Directed peptides C-terminal modification enabled by the engineered biomolecular catalyst-peptide amidase 12 B has been achieved via computational protein engineering. The engineered enzyme exhibits great promising potential in the C-terminal modification of opioid peptides using prop-2-yn-1-amine(PYA) or prop-2-en-l-amine(PEA) as the nucleophile. A variety of opioid peptides could be readily functionalized at the C-terminal chain in high yield in a mild and selective manner. Notably, modified opioid peptides bearing alkynyl moiety could be further functionalized through well-established click reaction.