Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors.     

蒜苔采后灰霉病害及生防拮抗菌的筛选研究

在蒜苔贮藏后期,从0℃冷库里发生灰霉病的蒜苔上分离到灰霉菌,经纯化和致病性鉴定得到灰霉属病原菌株。并且在其中并未发病的蒜苔分离到16种拮抗细菌,通过平板筛选法筛选出4株对灰霉菌具有拮抗作用的细菌,这4株拮抗菌在平板上对灰霉病菌的抑制力分别为:63.5%、47.6%、41.3%、38.1%。     

Exploitation of microbial antagonists for the control of postharvest diseases of fruits: a review

Fungal diseases result in significant losses of fruits and vegetables during handling, transportation and storage. At present, post-production fungal spoilage is predominantly controlled by using synthetic fungicides. Under the global climate change scenario and with the need for sustainable agriculture, biological control methods of fungal diseases, using antagonistic microorganisms, are emerging as ecofriendly alternatives to the use of fungicides. The potential of microbial antagonists, isolated from a diversity of natural habitats, for postharvest disease suppression has been investigated. Postharvest biocontrol systems involve tripartite interaction between microbial antagonists, the pathogen and the host, affected by environmental conditions. Several modes for fungistatic activities of microbial antagonists have been suggested, including competition for nutrients and space, mycoparasitism, secretion of antifungal antibiotics and volatile metabolites and induction of host resistance. Postharvest application of microbial antagonists is more successful for efficient disease control in comparison to pre-harvest application. Attempts have also been made to improve the overall efficacy of antagonists by combining them with different physical and chemical substances and methods. Globally, many microbe-based biocontrol products have been developed and registered for commercial use. The present review provides a brief overview on the use of microbial antagonists as postharvest biocontrol agents and summarises information on their isolation, mechanisms of action, application methods, efficacy enhancement, product formulation and commercialisation.     

咪达那新的合成研究进展

对咪达那新的合成方法进行了归纳和比较,重点介绍了关键中间体4-(2-甲基-1-咪唑基)-2,2-二苯基丁腈的合成及由关键中间体合成咪达那新的研究进展,为咪达那新的进一步研究及工业化生产提供参考。     

BAK和BAG-1蛋白在结直肠癌中的表达及其意义

目的探讨BAK和BAG-1蛋白在结直肠癌中的表达及其意义。方法采用免疫组化SP法对80例结直肠癌、40例结直肠腺瘤及25例癌旁正常结直肠黏膜组织中BAK和BAG-1蛋白的表达进行检测,并分析其与结直肠癌临床病理特征之间的相关性。结果 BAK和BAG-1蛋白在结直肠癌中过度表达,表达率分别为72.5%(58/80)和80%(64/80),且BAG-1蛋白与肿瘤的分化程度呈负相关,BAK蛋白与肿瘤的分化程度呈正相关。有淋巴结转移的结直肠癌,其BAG-1蛋白的表达率为96.7%(29/30),无淋巴结转移的结直肠癌,其BAG-1蛋白的表达率为70%(35/50),两者相比差异有统计学意义(P<0.01)。结论 BAK和BAG-1蛋白的过度表达与肿瘤的分化程度密切相关,且BAG-1蛋白的过度表达还与肿瘤的淋巴结转移密切相关;结直肠癌的发生机制可能涉及BAK和BAG-1调节环路中多个基因的异常。     

Interplay between Endothelin and Erythropoietin in Astroglia: The Role in Protection against Hypoxia

We show that, under in vitro conditions, the vulnerability of astroglia to hypoxia is reflected by alterations in endothelin (ET)-1 release and capacity of erythropoietin (EPO) to regulate ET-1 levels. Exposure of cells to 24 h hypoxia did not induce changes in ET-1 release, while 48–72 h hypoxia resulted in increase of ET-1 release from astrocytes that could be abolished by EPO. The endothelin receptor type A (ETA) antagonist BQ123 increased extracellular levels of ET-1 in human fetal astroglial cell line (SV-FHAS). The survival and proliferation of rat primary astrocytes, neural precursors, and neurons upon hypoxic conditions were increased upon administration of BQ123. Hypoxic injury and aging affected the interaction between the EPO and ET systems. Under hypoxia EPO decreased ET-1 release from astrocytes, while ETA receptor blockade enhanced the expression of EPO mRNA and EPO receptor in culture-aged rat astroglia. The blockade of ETA receptor can increase the availability of ET-1 to the ETB receptor and can potentiate the neuroprotective effects of EPO. Thus, the new therapeutic use of combined administration of EPO and ETA receptor antagonists during hypoxia-associated neurodegenerative disorders of the central nervous system (CNS) can be suggested.     

1,4—二氢吡啶类钙拮抗剂的合成法研究——(Ⅰ)尼群地平改进合成工艺

间硝基亚苄基乙酰乙酸乙酯与3-氨基丁烯酸甲酯在原位形成的哌啶乙酸盐的催化下经Michael加成反应环合制得尼群地平。对关键中间体间硝基亚苄基乙酰乙酸乙酯的制备进行了改进。以间硝基苯甲醛计算,总收率93％。此法原料易得,反应条件温和,适合工业化生产。     

Hypomagnesemia as a predictor of mortality in hemodialysis patients and the role of proton pump inhibitors: A cross‐sectional, 1‐year,retrospective cohort study

Introduction This study aimed to evaluate the association between proton pump inhibitor (PPI) use and serum magnesium levels, and the role of hypomagnesemia and PPI use as a risk factor for mortality in hemodialysis patients. Methods An observational study, including a cross‐sectional and 1‐year retrospective cohort study. The study comprised 399 hemodialysis patients at a single center, and was conducted from January to September 2014. Multiple linear regression analysis was used to investigate the independent relationship between serum magnesium levels and baseline demographic and clinical variables, including PPI and histamine‐2 receptor antagonist use. Cox regression model was used to identify lower serum magnesium level and PPI as a predictor of 1‐year mortality. Findings Serum magnesium levels were lower with PPI use than non‐PPI use (2.39 ± 0.36 vs. 2.56 ± 0.39 mg/dL, P < 0.001). Multiple linear regression analysis showed that PPI use, low serum albumin levels, and low serum potassium and high‐sensitivity C‐reactive protein (hs‐CRP) levels were significantly associated with low serum magnesium levels. A total of 29 deaths occurred during the follow‐up period. According to Cox regression analysis stratified by hs‐CRP, only high serum hs‐CRP levels (>4.04 mg/L) in association with low serum magnesium levels was an independent risk factor for 1‐year mortality (hazard ratio: 2.92; 95% CI: 1.53–6.40, P < 0.001). Discussion Serum magnesium levels are lower in PPI use. In the inflammatory state, a low serum magnesium level is a significant predictor of mortality in hemodialysis patients.     

Simultaneous Disruption of Pheromone Communication in Choristoneura rosaceana and Pandemis limitata with Pheromone and Antagonist Blends

In British Columbia, trapping and wind-tunnel studies demonstrated that (Z)-9-tetradecenyl acetate (Z9–14:OAc), a minor component of the sex pheromone for Pandemis limitata, acted as a pheromone antagonist to a sympatric species, Choristoneura rosaceana. Addition of >1% Z9–14:OAc to the four-component C. rosaceana pheromone in a wind tunnel resulted in significant reductions in the proportion of male C. rosaceana that wing fanned, locked on to the plume in flight, oriented upwind, and made source contact, compared to the responses to the pheromone alone. Disruption of pheromone communication was tested in 33.3 × 33.3-m plots, at a release rate of 10 mg/ha/hr using Conrel fiber dispensers. Z9–14:OAc applied alone did not disrupt orientation to virgin-female-baited traps for either C. rosaceana or P. limitata. A 1:1 mixture of Z9–14:OAc and the four-component C. rosaceana pheromone was as effective as the pheromone alone at disrupting orientation of C. rosaceana males to virgin-female-baited traps, demonstrating that disruption apparently did not occur through false-trail following. The 1:1 mixture of Z9–14:OAc and the C. rosaceana pheromone also reduced catches of P. limitata males in virgin-female-baited traps, but not significantly more than the 83% disruption caused by the pheromone alone. Therefore, the C. rosaceana pheromone could be used alone or with Z9–14:OAc to disrupt communication and, presumably, mating in both leafrollers simultaneously.     

Interleukin-1 Receptor Antagonist Reduces Neonatal Lipopolysaccharide-Induced Long-Lasting Neurobehavioral Deficits and Dopaminergic Neuronal Injury in Adult Rats

Our previous study showed that a single lipopolysaccharide (LPS) treatment to neonatal rats could induce a long-lasting neuroinflammatory response and dopaminergic system injury late in life. This is evidenced by a sustained activation of microglia and elevated interleukin-1β (IL-1β) levels, as well as reduced tyrosine hydroxylase (TH) expression in the substantia nigra (SN) of P70 rat brain. The object of the current study was to test whether co-administration of IL-1 receptor antagonist (IL-1ra) protects against LPS-induced neurological dysfunction later in life. LPS (1 mg/kg) with or without IL-1ra (0.1 mg/kg), or sterile saline was injected intracerebrally into postnatal day 5 (P5) Sprague-Dawley male rat pups. Motor behavioral tests were carried out from P7 to P70 with subsequent examination of brain injury. Our results showed that neonatal administration of IL-1ra significantly attenuated LPS-induced motor behavioral deficits, loss of TH immunoreactive neurons, as well as microglia activation in the SN of P70 rats. These data suggest that IL-1β may play a pivotal role in mediating a chronic neuroinflammation status by a single LPS exposure in early postnatal life, and blockading IL-1β might be a novel approach to protect the dopaminergic system against perinatal infection/inflammation exposure.