Isolation,identification, semi-synthesis of aziditaxel derivatives and their biological evaluation

Two new taxoids (5 and 6) were obtained by isolating impurities in aziditaxel, and their structures were characterized based on data analysis of ¹H NMR, ¹³C NMR, HPLC-MS, and through comparison with literature. In order to test their cytotoxicities against human nonsmall lung cancer cell lines (A549), sufficient amounts of compounds 5 and 6 were obtained by semi-synthesis and both of them showed equipotent cytotoxiesty compared with taxol, docetaxel, and aziditaxel.     

Serotonin Modulates Ethanol-Induced Depression in Cerebellar Purkinje Neurons

In the present study, we found that local application of serotonin (5-HT) potentiated ethanol-induced depressions of the spontaneous activity of Purkinje neurons in urethane-anesthetized rats. 5-HT also potentiated depressions induced by γ-aminobutyric acid; however, this modulatory response was quantitatively smaller than 5-HT-induced potentiation of ethanol depression. Previous reports suggested that the release of 5HT can be regulated by presynaptic 5-HT autoreceptors. We found that local application of methiothepin, which may induce 5-HT overflow through the inhibition of presynaptic autoreceptors, facilited ethanol-mediated responses. This methiothepin effect was greatly diminished in neonatally 5,7-dihydroxyhyptamine-lesioned animals, suggesting a presynaptic mechanism was involved. We also found that the 5-HT_IAantagonist UH301 did not attenuate 5-HT-facilitated ethanol reactions. On the other hand, local application of SHT_IB agonist CGS12066B potentiated ethanol-induced depression. Taken together, our data suggest that 5-HT can modulate ethanol-mediated electrophysiological depression, possibly mediated through CHT, receptors in the cerebellum.     

Enhanced neuropeptide Y immunoreactivity and vasoconstriction in mesenteric small arteries from spontaneously hypertensive rats

Enhanced sympathetic nerve activity is thought to play a role in the pathogenesis of hypertension. The purpose of the present study was to investigate the mechanisms underlying the enhanced vasocontractile response to perivascular stimulation of mesenteric arteries isolated from female spontaneously hypertensive rats (SHR). Innervation of mesenteric small arteries was evaluated by immunohistochemistry and confocal microscopy while functional studies were conducted in a microvascular myograph. The distribution of nerve terminals immunoreactive for tyrosine hydroxylase (TH) and neuropeptide Y (NPY) was similar in mesenteric small arteries from Wistar-Kyoto (WKY) and SHR rats. However, immunointensity of TH or NPY immunoreactivities were much higher in small arteries from SHR compared to WKY. Expressed as percentage of contractions elicited by 124 mM K(+), concentration-response curves for noradrenaline (NA) and NPY were shifted leftward in SHR compared with WKY rats. The combination of noradrenaline (1 microM) and NPY (10 nM) contracted mesenteric arteries from WKY and SHR to higher levels than compared to either contractile agent added alone. The NPY Y(1) receptor antagonist, BIBP 3226, inhibited these contractions with 87 +/- 0.7 and 80 +/- 1.3% (p < 0.05, n = 6) in arteries from WKY and SHR rats, respectively. In arteries incubated with the alpha(1)-adrenoceptor antagonist, prazosin, and preactivated with vasopressin, electrical field stimulation evoked contractions which were more pronounced in mesenteric arteries from SHR compared to WKY rats. BIBP 3226 partially inhibited these contractions. In vasopressin-activated arteries BIBP 3226 caused rightward shifts of the concentration-response curves for NPY in mesenteric arteries from SHR rats, but in addition it also abolished the maximal NPY contraction in arteries from WKY rats. In the presence of BIBP 3226, low concentrations (1 pM to 10 nM) of NPY caused relaxations in arteries from WKY, but not in segments from SHR rats. Mechanical removal of the endothelium abolished NPY relaxation in arteries from WKY. In arteries activated with vasopressin and exposed to either forskolin or sodium nitroprusside, the addition of NPY evoked contractions which were more pronounced in arteries from SHR compared to WKY arteries. The present study suggests that enhanced NPY content and vasoconstriction to NPY in arteries from hypertensive rats can contribute to the enhanced sympathetic nerve activity and vascular resistance in female hypertensive rats. Endothelial cell dysfunction as well as alterations in smooth muscle response to NPY seem to contribute to the enhanced vasoconstriction in arteries from hypertensive animals.     

Factors associated with mental health of graduate nursing students in China

The increasing number of graduate nursing students in China has resulted in the wide concern for their mental health problems. Quantitative studies using validated questionnaires on mental health of graduate nursing students are rare. This study aimed to investigate the factors potentially involved in the level of mental health of graduate nursing students.The sample consisted of 339 graduate nursing students from 5 universities of China. The participants were evaluated using the Symptom Checklist-90 (SCL-90) and Chinese Perceived Stress Scale (CPSS) between March and November 2020. Multivariate stepwise linear regression analysis and spearman correlation test were performed to assess the association between various factors associated with mental health.The SCL-90 total score was 109.00 (96.00 –134.00) and psychological abnormalities (total score > 160) accounted for 14.2%. The highest score in the nine dimensions was compulsion dimension. The positive detection rate of compulsion dimension was 21.5% (dimensions score > 2),and the average of compulsion score was 1.50(1.20 –2.00). Multivariable stepwise linear regression analysis showed that grade, environmental adaptation level, number of good friends were independently associated with lower SCL-90 scores (both P < .05). SCL-90 scores were correlated with Chinese Perceived Stress Scale (r = .159, P = .003).Results indicate that learning about ways to adapt to the environment, strengthening good friends support and alleviating perceived stress can help improve graduate nursing students’ level of mental health. The conclusions of this study can provide a reference to improve the psychological intervention strategies for graduate nursing students.     

他汀类药物在中国极高危冠心病患者二级预防中的应用现况

目的 通过了解中国内地31个省市门诊极高危冠心病患者调脂治疗状况,评价我国极高危冠心病患者二级预防重点措施的临床应用与指南的差距.方法 2006年在中国内地31个省市自治区选择32家三级医院和32家二级医院,每家医院从研究启动时点开始连续收集门诊极高危冠心病患者50例.采用访谈形式收集患者的信息,填写统一表格.结果 在2516例门诊极高危冠心病患者中,男性1746例,女性770例,年龄(65±10)岁.门诊极高危冠心病患者本次就诊前他汀类药物的服用率为[57.9%(1456/2516)],其中男性高于女性[60.5%(1056/1746)比51.9%(400/770),P＜0.01],三级医院患者高于二级医院患者[65.0%(858/1320)比50.0%(598/1196),P＜0.01].低密度脂蛋白胆固醇的达标率为29.8%(537/1803),三级医院高于二级医院[32.2%(309/959)比27.0%(228/844),P＜0.05],7个地区(华北、华东、华南、华中、东北、西南和西北)中,华中地区达标率最高[38.5%(77/200)],东北地区最低[18.5%(34/184)].本次就诊时,68.2%(1713/2511)的患者获得医生的他汀类药物处方,其中84.4%(1437/1703)处方为原研他汀类药物,75.9%(1256/1655)的他汀类药物处方剂量符合指南推荐的标准剂量.结论 我国内地门诊极高危冠心病患者低密度脂蛋白胆固醇控制状况与指南有一定差距,且不同级别医院、不同地区之间存在明显差异.     

Rapid glia expression and release of proinflammatory cytokines in experimental Klebsiella pneumoniae meningoencephalitis

The host immune/inflammatory response following CNS infection by Klebsiella pneumoniae remains poorly understood. Using a rat model of K. pneumoniae meningoencephalitis, we investigated the temporal profiles of brain proinflammatory cytokines and their cellular sources. Leukocyte counts significantly increased in cerebrospinal fluid (CSF) at 2 h after K. pneumoniae inoculation into the rat brain but were still much lower than blood leukocyte counts. However, concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 in CSF were much higher than the simultaneously collected serum levels. The rapid increase in brain expression of these cytokines at the messenger RNA (mRNA) and protein levels occurred earlier than the onset of leukocytosis. Double immunofluorescence staining revealed the presence of TNF-alpha, IL-1beta, and IL-6 in astrocytes and microglia. Exposure of primary culture of glial cells to K. pneumoniae also resulted in time-dependent increases in the concentration of these cytokines in the culture media. Taken together, our results suggest that glial cells are an important early source of proinflammatory cytokines during K. pneumonia infection of CNS.     

A simple method for large-scale generation of dopamine neurons from human embryonic stem cells

Dopamine (DA) neurons derived from human embryonic stem cells (hESCs) are potentially valuable in drug screening and as a possible source of donor tissue for transplantation in Parkinson's disease. However, existing culture protocols that promote the differentiation of DA neurons from hESCs are complex, involving multiple steps and having unreliable results between cultures. Here we report a simple and highly reproducible culture protocol that induces expandable DA neuron progenitors from hESCs in attached cultures. We found that the hESC-derived neuronal progenitors retain their full capacity to generate DA neurons after repeated passaging in the presence of basic fibroblast growth factor (bFGF) and medium conditioned with PA6 stromal cells. Using immunocytochemistry and RT-PCR, we found that the differentiated DA neurons exhibit a midbrain phenotype and express, e.g., Aldh1a, Ptx3, Nurr1, and Lmx1a. Using HPLC, we monitored their production of DA. We then demonstrated that the expanded progenitors are possible to cryopreserve without loosing the dopaminergic phenotype. With our protocol, we obtained large and homogeneous populations of dopaminergic progenitors and neurons. We conclude that our protocol can be used to generate human DA neurons suitable for the study of disease mechanisms, toxicology, drug screening, and intracerebral transplantation.