American ginseng: Potential structure-function relationship in cancer chemoprevention

Ginseng has a prominent position on the list of best-selling herbal products in the world, and its main active constituents are thought to be ginsenosides. Compared with the long history of use and widespread research on Asian ginseng, studies of American ginseng are relatively limited, especially regarding cancer chemoprevention. In recent studies of American ginseng, steaming or heating altered the ginsenoside profile and thereby increased anticancer effects. Yet the ginsenoside structures and their activities have not been systematically elucidated. In this commentary, we introduce the different ginsenosides in American ginseng, both the naturally occurring compounds and those resulting from steaming or biotransformation. We briefly review American ginseng's reported anticancer effects and their mechanisms of action, and explore the possible structural-function relationship with a focus on sugar molecules, hydroxyl groups and stereoselectivity in ginsenosides. Understanding these relationships may produce insights into chemical and pharmacological approaches for enhancing the chemopreventive effects of ginsenoside and for developing novel anticancer agents.     

Antiviral activity of aliphatic nucleoside analogues: structure-function relationship.

Of a series of 58 aliphatic nucleoside analogues, (S)-9-(2,3-dihydroxypropyl)adenine [(S)-DHPA] proved to be the most active congener, when assayed for antiviral activity in primary rabbit kidney cell cultures challenged with either vaccinia or vesicular stomatitis virus. Whereas most analogues derived from substituted purine and pyrimidine bases and bearing various hydroxy- or amino-substituted alkyl chains did not show evidence of antiviral activity at a concentration of 2 mM, (S)-DHPA inhibited both vaccinia and vesicular stomatitis virus replication at 0.05-0.1 mM. For 9-[(RS)-2,3-diazidopropyl]adenine and some di- and trihydroxybutyl analogues of DHPA, viz., 9-[(2RS,3SR)-2,3-dihydroxybutylladenine, 9-[(RS)- or 9-[(S)-3,4-dihydroxybutyl]adenine, 9-[(2S,3R)-2,3,4-trihydroxybutyl]adenine, and 3-(adenin-9-yl)-(RS)-alanine, an antiviral effect was noted at a concentration of 0.5-1 mM.     

Progress in understanding the relationship between the pharmacological effects of nicotine and human tobacco dependence

The present paper is intended to serve as an introduction to the series of eight papers which follow in this issue of Pharmacology Biochemistry and Behavior. A brief historical review of research that is at the root of much recent progress is provided in the present paper. In addition, we provide some data which illustrates the scope of tobacco-related research, world wide, in an effort to provide a perspective as to the vast amount of research activity that is currently in progress. Seven of the papers which follow were presented at a symposium held under the auspices of the American Society for Pharmacology and Therapeutics in 1986. Taken together, these papers are intended to provide new data and to review major areas of pharmacologic research relevant to the understanding and treatment of tobacco dependence. The topics include the behavioral and physiologic mechanisms by which the effects of nicotine are mediated, metabolic aspects of nicotine kinetics, and genetic determinants of responses to nicotine. The final paper is a discussion of the implications of these recent data for the pharmacologic treatment of tobacco dependence.     

多肽调控因子AcSDKP的生物学活性及构效关系研究进展

AcSDKP是从胎牛骨髓中提取的一种以细胞生长抑制作用为主的多功能生理调控因子，不仅具有抑制造血干细胞生长的生物学功能，对淋巴细胞、肝细胞、肾间质成纤维细胞及心肌成纤维细胞等多种细胞均有增殖抑制作用。同时还能介导血管的生成，对生殖系统也有明显刺激作用，可促进精子生成。本文就AcSDKP的多种生物学活性及最新研究进展作一综述。     

Towards addiction as relationship

In this article, we wish to offer some thoughts on the taken-for-granted connotations of the term ‘addiction’, and on the limits of the disease model which these assumptions support, and by way of comparison with parallel developments in the field of ‘schizophrenia’ research, to suggest some avenues for conceptual development.     

Probing the structure-function relationship of polyene macrolides: engineered biosynthesis of soluble nystatin analogues

Although polyene macrolides are efficient antifungal agents with fungicidal mode of action, their use in medical practice is problematic due to their low solubility and significant human toxicity. In an attempt to address the solubility problem, we have obtained two analogues of nystatin with hydroxy groups at positions C31 and C33 through manipulation of the nystatin polyketide synthase in the producing organism Streptomyces noursei. Structures of the analogues were confirmed by nuclear magnetic resonance (NMR), and their solubility was found to be more than 2000 times higher than that of nystatin. However, both analogues were shown to have lost antifungal activity, implying that the integrity of the hydrophobic polyene region of the nystatin molecule is crucial for the fungicidal action. NMR data and computer modeling performed for the new analogues suggested conformational changes together with a significantly increased structural disorder, which may account for both increased solubility and the loss of activity.     

Benzofuranone derivatives as effective small molecules related to insulin amyloid fibrillation: a structure-function study

Amyloids are protein fibrils of nanometer size resulting from protein self-assembly. They have been shown to be associated with a wide variety of diseases such as Alzheimer's and Parkinson's and may contribute to various other pathological conditions, known as amyloidoses. Insulin is prone to form amyloid fibrils under slightly destabilizing conditions in vitro and may form amyloid structures when subcutaneously injected into patients with diabetes. There is a great deal of interest in developing novel small molecule inhibitors of amyloidogenic processes, as potential therapeutic compounds. In this study, the effects of five new synthetic benzofuranone derivatives were investigated on the insulin amyloid formation process. Protein fibrillation was analyzed by thioflavin-T fluorescence, Congo red binding, circular dichroism, and electron microscopy. Despite high structural similarity, one of the five tested compounds was observed to enhance amyloid fibrillation, while the others inhibited the process when used at micromolar concentrations, which could make them interesting potential lead compounds for the design of therapeutic antiamyloidogenic compounds.     

Receptors for ATP in rat sensory neurones: the structure-function relationship for ligands.

1. Rat isolated tracheal smooth muscle preparations respond to phospholipase A2 (PLA2) and phospholipase C (PLC) with contractile responses of highly variable magnitudes. Rat tracheae exposed to PLA2 or PLC for a period of 10-30 min, exhibit airway hyperreactivity (AH) to cooling (10 degrees C), i.e., respond with strong contractile responses. Phospholipase D neither contracted rat tracheae nor induced AH to cooling. 2. PLA2-induced AH to cooling was dependent on the presence of extracellular Ca2+ in the physiological solution. 3. Verapamil, azelastine, diltiazem and TMB-8 (each 10 microM) significantly attenuated PLA2-induced AH. This effect was not shared by nifedipine (10 microM). 4. Bepridil (10 microM), a Ca2+ and calmodulin antagonist, also significantly attenuated AH induced by PLA2. 5. Indomethacin (a cyclo-oxygenase inhibitor), AA-861 (a selective 5-lipoxygenase inhibitor), FPL 55712 (a leukotriene receptor antagonist), methysergide (a 5-hydroxytryptamine D-receptor antagonist) and pyrilamine (a histamine H1-receptor antagonist) exerted little or no effect on PLA2-induced AH to cooling. 6. Atropine significantly attenuated PLA2-induced AH suggesting the participation of acetylcholine. 7. Nordihydroguaiaretic acid (an antioxidant; 5-lipoxygenase inhibitor) and BW 755C (an antioxidant; a dual inhibitor of cyclo-oxygenase and 5-lipoxygenase) significantly attenuated PLA2-induced AH to cooling. 8. In conclusion, these data show that PLA2 (an enzyme involved in the synthesis of Paf-acether, prostaglandins, thromboxanes, leukotrienes, diacylglycerol, superoxide free radicals and lipid peroxides, etc.) induces AH to cooling and acetylcholine in rat trachea. The induction of AH to cooling is dependent on the presence of extracellular Ca2+ and is significantly attenuated by verapamil, diltiazem, bepridil, atropine and azelastine (an antiallergic/antiasthmatic drug).     

Molecular modeling on structure-function analysis of human progesterone receptor modulators

Considering the significance of progesterone receptor (PR) modulators, the present study is explored to envisage the biophoric signals for binding to selective PR subtype-A using ligand-based quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies on nonsteroidal substituted quinoline and cyclocymopol monomethyl ether derivatives. Consensus QSAR models (Training set (Tr): n(Tr)=100, R(2) (pred)=0.702; test set (Ts): n(Ts)=30, R(2) (pred)=0.705, R(2) (m)=0.635; validation set (Vs): n(Vs)=40, R(2) (pred)=0.715, R(2) (m)=0.680) suggest that molecular topology, atomic polarizability and electronegativity, atomic mass and van der Waals volume of the ligands have influence on the presence of functional atoms (F, Cl, N and O) and consequently contribute significant relations on ligand binding affinity. Receptor independent space modeling study (Tr: n(Tr)=26, Q(2)=0.927; Ts: n(Ts)=60, R(2) (pred)=0.613, R(2) (m)=0.545; Vs: n(Vs)=84, R(2) (pred)=0.611, R(2) (m)=0.507) indicates the importance of aromatic ring, hydrogen bond donor, molecular hydrophobicity and steric influence for receptor binding. The structure-function characterization is adjudged with the receptor-based docking study, explaining the significance of the mapped molecular attributes for ligand-receptor interaction in the catalytic cleft of PR-A.     

Towards Alzheimer's disease vaccination

Active and passive immunization against fibrillar beta-amyloid of various mice models of Alzheimer's disease leads to the disaggregation and inhibition of plaque formation. Preliminary results showing improved behaviour and memory function obtained after administration of anti-beta-amyloid vaccines to transgenic mice encourage these and related approaches for testing in the treatment and prevention of Alzheimer's disease.     

Towards improved therapeutic CORMs: understanding the reactivity of CORM-3 with proteins

The biological role of carbon monoxide (CO) has completely changed in the last decade. Beyond its widely feared toxicity, CO has revealed a very important biological activity as a signaling molecule with marked protective actions namely against inflammation, apoptosis and endothelial oxidative damage. Its direct use as a therapeutic gas showed significant and consistent positive results but also intrinsic severe limitations. The possibility of replacing the gas by pro-drugs acting as CO-Releasing Molecules (CO-RMs) has clearly been demonstrated with several experimental compounds. Transition metal carbonyls complexes have proven to be the most versatile experimental CO-RMs so far. Presently, the challenge is to equip them with drug-like properties to turn them into useful pharmaceuticals. This requires studying their interactions with biological molecules namely those that control their pharmacokinetic and ADME profiles like the plasma proteins. In this account we analyze these questions and review the existing interactions between Metal Carbonyls and proteins. The recently explored case of CORM-3 is revisited to exemplify the methodologies involved and the importance of the results for the understanding of the mode of action of such pro-drugs.     

血清淀粉样蛋白A与慢性阻塞性肺病急性加重期的关系及临床意义

目的观察慢性阻塞性肺病急性加重期（AECOPD）患者的血清淀粉样蛋白A（SAA）、C反应蛋白（CRP）水平变化以及临床意义。方法选择56例AECOPD患者,检测入院时、缓解时、稳定期及对健康对照者SAA、CRP。结果（1）入院时SAA、CRP显著高于稳定期及正常对照组（P值均〈0．05）;（2）Ⅲ级组入院时SAA水平较Ⅰ/Ⅱ级组显著升高（P〈0．05）,CRP无显著差异;（3）治疗失败组入院时SAA水平较治疗缓解组显著升高（P〈0．05）,CRP无显著差异;（4）入院时SAA水平与住院时间有显著正相关性,CRP无相关性。结论本研究表明SAA可作为AECOPD的炎症标志物。     

巨细胞病毒感染与冠心病关系的临床研究

目的　探讨人类巨细胞病毒 (HCMV)感染与冠心病的关系。方法　采用间接ELISA法检测其外周血巨细胞病毒抗体 ,同时应用免疫透射比浊法测定其C反应蛋白的水平。结果　冠心病组 6 0例 ,外周血巨细胞病毒抗体IgG阳性 2 6例 (4 3 3% ) ,健康对照组 6 0例中阳性 10例 (16 6 % ) ,两组比较差异有显著意义 (P <0 0 5 )。HCMV抗体阳性者 2 6例同时检测外周血CRP水平大于正常者 2 0例 (76 9% ) ,正常对照组2 6例CRP水平大于正常者 3例 (11 5 % ) ,两组比较差异有显著意义 (P <0 0 1)。结论　巨细胞病毒感染与冠心病之间关系密切。     

人类巨细胞病毒感染与冠心病关系的临床研究

目的探讨人类巨细胞病毒（HCMV）感染与冠心病间的关系以及可能的炎性免疫机制。方法采用聚合酶链反应（PCR）检测冠心病30例（急性心肌梗死10例,陈旧性心肌梗死5例,心绞痛15例）及正常对照30例外周血中的HCMV-DNA,放射免疫法测定血浆内皮素（ET）、血清肿瘤坏死因子-α（TNF-α）、白介素-1β（IL-1β）和白介素-8（IL-8）水平。结果冠心病组HCMV-DNA检出率（70％）明显高于正常对照组（20％,P〈0．01）,各亚组间无显著性差异。冠心病组ET、TNF-α、IL-1β和IL-8水平均明显高于对照组（P〈0．01）,且各亚组间存在着良好的正相关,与冠脉造影对比均随病变血管数增多而升高;心绞痛亚组IL-8水平明显低于心肌梗死,与对照组问无显著性差异（P〉0．05）。结论HCMV感染可能是冠心病的一个重要的致病因子,其感染所触发的炎性免疫反应在冠心病的发生发展中可能起重要的作用。