Synthesis,in vivo and in silico evaluation of novel 2,3-dihydroquinazolin-4(1H)-one derivatives as potential anticonvulsant agents

In light of the pharmacophoric structural requirements for achieving anticonvulsant activity, a series of N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)benzamide (4a-g) and N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)-2-phenylacetamide (4h-n) derivatives were synthesized in two steps starting from the reaction of N-methyl isatoic anhydride with the appropriate hydrazide and followed by condensation with the appropriate aldehyde. The anticonvulsant activities of the synthesized compounds were evaluated according to the anticonvulsant drug development (ADD) programme protocol. Among the synthesized compounds, 4n showed promising activity in both the maximal electroshock (MES) and pentylenetetrazole (PTZ) tests with median effective dose (ED₅₀) values of 40.7 and 6 mg/kg, respectively. The six most promising derivatives, 4b , 4a , 4c , 4f , 4j , and 4i , showed very low ED₅₀ values in the PTZ test (3.1, 4.96, 8.68, 9.89, 12, and 13.53 mg/kg, respectively). All the tested compounds showed no to low neurotoxicity in the rotarod test with a wide therapeutic index. Docking studies of compound 4n suggested that GABA_A binding could be the mechanism of action of these derivatives. The in silico drug likeliness parameters indicated that none of the designed compounds violate Lipinski's rule of five and that they are able to cross the blood–brain barrier.

Spread of an Enterococcus faecalis sequence type 6 (CC2) clone in patients undergoing selective decontamination of the digestive tract

Enterococcus faecalis (E. faecalis) is a common cause of nosocomial infection in immunocompromised patients. The presence and dissemination of high‐risk clonal complexes, such as CC2, is an ongoing problem in hospitals. The aim of this work was to characterize 24 E. faecalis isolates from ICU patients undergoing selective decontamination of the digestive tract (SDD) by phenotypical (antimicrobial susceptibility) and genotypical (presence of virulence genes, RAPD‐PCR and MLST) methods. Our results showed high prevalence of the ST6 E. faecalis clone (91.6%), especially adapted to the hospital environment, with a multidrug resistance pattern and a multitude of putative virulence genes. In addition, ST179 (4.2%) and ST191 (4.2%) were detected. By RAPD–PCR analysis, the 22 isolates identified as ST6 showed six different DNA patterns, while the two remaining isolates, ST179 and ST191, showed two additional profiles. CC2 is a known clonal complex with high adaptability to hospital environment and worldwide distribution. The high prevalence of the ST6 clone in the studied population could be related to the presence of gentamicin in the SDD mixture since most strains were gentamicin resistant. Consequently, strict surveillance should be applied for rapid detection and control of this clone to prevent future spread outside the ICU.     

Sensory evoked potentials in patients with Rett syndrome through the lens of animal studies: Systematic review

ObjectiveSystematically review the abnormalities in event related potential (ERP) recorded in Rett Syndrome (RTT) patients and animals in search of translational biomarkers of deficits related to the particular neurophysiological processes of known genetic origin (MECP2 mutations).MethodsPubmed, ISI Web of Knowledge and BIORXIV were searched for the relevant articles according to PRISMA standards.ResultsERP components are generally delayed across all sensory modalities both in RTT patients and its animal model, while findings on ERPs amplitude strongly depend on stimulus properties and presentation rate. Studies on RTT animal models uncovered the abnormalities in the excitatory and inhibitory transmission as critical mechanisms underlying the ERPs changes, but showed that even similar ERP alterations in auditory and visual domains have a diverse neural basis. A range of novel approaches has been developed in animal studies bringing along the meaningful neurophysiological interpretation of ERP measures in RTT patients.ConclusionsWhile there is a clear evidence for sensory ERPs abnormalities in RTT, to further advance the field there is a need in a large-scale ERP studies with the functionally-relevant experimental paradigms.SignificanceThe review provides insights into domain-specific neural basis of the ERP abnormalities and promotes clinical application of the ERP measures as the non-invasive functional biomarkers of RTT pathophysiology.     

Immunohistochemical and molecular analysis of PI3K/AKT/mTOR pathway in esophageal carcinoma

Among the numerous signaling pathways involved in tumorigenesis, PI3K‐AKT‐mTOR is a key one that regulates diverse cellular functions. However, its prognostic value in esophageal carcinoma remains unclear. In our study, we examined the immunohistochemical expression of phosphorylated (p‐) AKT, mTOR, p70S6K and 4E‐BP1 along with the mutational status of PIK3CA and AKT1 genes by High Resolution Melting Analysis and Pyrosequencing in 44 esophageal carcinomas. The results were correlated with the clinicopathological characteristics of the patients in an effort to define their possible prognostic significance. Total p‐mTOR cytoplasmic expression, assessed in 10 random areas, was positively correlated with tumor stage (Kruskal–Wallis ANOVA, I/II vs III/IV, p = 0.0500). Μoreover, maximum p‐mTOR cytoplasmic immunoexpression, estimated in hot spot areas, was positively associated with tumor grade (Mann–Whitney U test, I/II vs III, p = 0.0565). Interestingly, p‐4E‐BP1 immunoreactivity was negatively correlated with tumor histological grade (Mann–Whitney U test, I/II vs III, p = 0.0427). No mutation was observed in exons 9 and 20 of PIK3CA gene and in exon 4 of AKT1 gene. In conclusion, our findings depict the presence of activated PI3K/AKT/mTOR pathway in esophageal cancer bringing forward p‐mTOR and p‐4E‐BP1 for their potential role in esophageal carcinogenesis. Additional studies are warranted to validate our findings.     

基于子宫内膜异位症与恶性肿瘤的相关性探析补肾化瘀法作用机制及中医理论依据

子宫内膜异位症其异位内膜组织虽然在形态学上呈良性表现，却具有类似恶性肿瘤的生物学特性。中医学一般认为，“正虚伏邪”为恶性肿瘤的病机特点；那么，肾虚血瘀既属于“正虚伏邪”的范畴，又体现了EMs发病学和疾病发生、发展过程中的主要特点。在“病证相应”的中医治则之下，补肾化瘀法的临床疗效主要表现为：缓解痛经症状、提高受孕率，以及调整月经周期。本文基于EMs与恶性肿瘤的相关性，通过分析补肾化瘀法治疗EMs的理论依据及其抑制异位内膜侵袭的调控机制，主要包括解除免疫抑制、阻断局部微血管新生等，旨在阐明其疗效显著的原因，为临床推广提供可靠的基础研究证据。     

A facile synthesis of [14C]pyrithiobac‐sodium

Condensation of thiourea 1 with diethyl malonate 2 in the presence of sodium methoxide furnished 4,6‐dihydroxy‐2‐mercaptopyrimidine 3 . Compound 3 on methylation with diazomethane followed by oxidation with H₅IO₆/CrO₃ in ethyl acetate gave 4,6‐dimethoxy‐2‐methylsulphonylpyrimidine 5 . Compound 5 on condensation with 2‐mercapto‐6‐chlorobenzoic acid in the presence of a phase transfer catalyst, tetrabutylammonium bromide and sodium carbonate gave the title compound – pyrithiobac‐sodium 6 with an overall yield of > 35% starting from thiourea. Following the above standardized procedure, using [¹⁴C]‐thiourea in lieu of thiourea, ¹⁴C labelled product 6 , was synthesized with an overall radiochemical yield > 30% (with respect to [¹⁴C]‐thiourea) for further evaluations of environmental fate of 6 , in soils and plants. Copyright © 2006 John Wiley & Sons, Ltd.     

APOE2 allele increased in tardive dyskinesia.

Ninety-seven inpatients with tardive dyskinesia (average AIMS score = 13), the majority of whom were schizophrenic, were studied. Forty patients were Caucasian, and 57 were African-American. The APOE genotypes of these patients were compared to previously published genotypes of controls and with previously published studies of APOE genotypes in patients with schizophrenia. There were no significant differences in APOE allele frequencies comparing the African-American tardive dyskinesia population and the African-American control groups. In contrast, significant (< 0.05) P values were obtained comparing the Caucasian tardive dyskinesia population to the Caucasian controls, when comparing allele frequencies and genotypic frequencies. This study suggests that Caucasians bearing an APOE2 allele are at increased risk of developing tardive dyskinesia, whereas African-Americans are not. APOE genotype-specific risks of both tardive dyskinesia and Alzheimer's disease that vary across populations could be due to recruitment of patients or controls or could be due to modifying effects of differing genetic or environmental backgrounds. The mechanism by which the APOE2 allele increases risk of tardive dyskinesia is not known. Further information about the mechanisms of increased risk of tardive dyskinesia could result in stratification of prescribing practices weighing the costs of medications against the relative risk of side effects.     

三列凹顶藻中倍半萜成分的研究

目的从三列凹顶藻Laurenciatristicha中寻找具有多样性结构的倍半萜化学成分,供药理活性筛选。方法采用凝胶柱色谱、硅胶柱色谱、重结晶和高效液相色谱等方法进行分离;借助包括一维和二维NMR等波谱方法和X-单晶衍射鉴定化合物的结构;用MTT法对得到的化合物进行细胞毒活性评价。结果分离得到5个倍半萜类化合物,分别鉴定为海兔阿普里素(aplysin,)、海兔阿普里醇(aplysinol,)、去溴海兔阿普里醇(debro-moaplysinol,)、凹顶藻联苯(laurebiphenyl,)、约翰斯顿醇(johnstonol,);在人肿瘤细胞株HCT-8、Bel-7402、BGc-823、A549和HeLa模型上,化合物对所有细胞株均显示毒性,化合物对HeLa细胞显示中等强度的细胞毒活性,其他化合物对所有细胞株均无明显毒性,IC50均大于10.0μg/mL。结论化合物~均为首次从三列凹顶藻中得到,化合物对HeLa细胞具有中等强度的选择性细胞毒活性,化合物对所有细胞株均显示毒性。