Structure-activity relationships of non-imidazole H(3) receptor ligands. Part 3: 5-Substituted 3-phenyl-1,2,4-oxadiazoles as potent antagonists

Further SAR studies on novel histamine H(3) receptor antagonists are presented. Compound 14bb is a potent antagonist of both the rat cortical and human clone receptors, and is demonstrated to act functionally as an antagonist in an in vivo mouse dipsogenia model.     

Clove Buds Volatile Compounds: Inhibitory Activity on Mycobacterium Growth and Molecular Docking on Mmr Efflux Pump Drug Resistance

Syzygium aromaticum is used in traditional and modern medicine for its various and outstanding pharmacological properties. Here, we studied the chemical composition of hexane extract and non-polar fractions (NPF) obtained from the maceration and fractionation of clove buds, in order to evaluate their in vitro antimycobacterial activity, as well as their contribution against efflux pump (EP) resistance through molecular docking experiments. The gas chromatography-mass spectrometry (GC–MS) analysis of the volatile profiles revealed the presence of eugenol, followed by eugenyl acetate, and β-caryophyllene as common major compounds. According to Resazurin microtiter assay (REMA), Mycobacterium tuberculosis H₃₇Rv strain was sensitive to all volatile samples at concentration range between 10 and 100 μg/mL. The NPF of ethanol extract was the best inhibitor with a MIC=10 μg/mL. The in silico study revealed a strong binding affinity between eugenol and Mmr EP protein (−8.1 Kcal/mol), involving two binding modes of hydrogen bond and π-alkyl interactions. The non-polarity character of clove volatile constituents, and their potential additive or synergistic effects could be responsible for the antimycobacterial activity. In addition, these findings suggest the benefic effect of eugenol in the management of mycobacterium drug resistance, whether as potential inhibitor of Mmr drug EP, or modulator during combination therapy.     

Listening to Music during Warming-Up Counteracts the Negative Effects of Ramadan Observance on Short-Term Maximal Performance

Aim

The aim of the present study was to examine whether listening to music during warming-up might influence short-term maximal performance (STMP), cognitive anxiety, self-confidence, and enjoyment during Ramadan, and whether these affects might predict STMP.

Methods

Nine male physical education students (age: 21 ± 1.1 years; height: 1.8 ± 0.04 m; body mass: 83 ± 5 kg) volunteered to participate in the present study. A within-subjects design consisted of four experimental sessions: Two sessions occurred one week before Ramadan and two others took place during Ramadan. They were scheduled at 5 p.m. and were conducted as follows: After a 10-minute warm-up either with or without listening to music, each participant performed a 5-m multiple shuttle run test, after which he was asked to answer items intended to assess his affective state during the experimental task.

Results

Our findings revealed that STMP was lower during Ramadan than before Ramadan in the no-music condition. Additionally, it was found that STMP was higher in the music condition than in the no-music condition during Ramadan, and that STMP measured before Ramadan did not differ from that measured during Ramadan in the music condition. Regarding affects, the findings revealed that enjoyment was lower during Ramadan than before Ramadan in the music condition, and that cognitive anxiety was lower in the music condition than in the no-music condition before Ramadan. Self-confidence was not influenced by the experimental conditions.

Conclusion

This study showed that listening to music during warming-up not only would be beneficial for STMP in Ramadan fasters, but also would counteract the negative effects of Ramadan observance on STMP.     

不同土地覆被格局情景下多种生态系统服务的响应与权衡——以雅砻江二滩水利枢纽为例

在二滩水库集水区,按照当地生态政策发展以坡度为指标构建了10种未来土地覆被格局情景,研究生态系统减轻水库泥沙淤积、减轻水库面源污染、产水发电服务及价值对未来覆被格局的响应程度,并兼顾相关产业收益的变化,权衡各种情景格局的服务效益,优选利益相关方福祉提升幅度最大的情景格局。结果表明:1)现有土地覆被格局对减轻水库泥沙淤积功效的发挥不合理,而以退耕还林政策指导区域土地覆被格局变化,对集水区减轻河道和水库泥沙淤积具有较好功效。10种情景下,保沙价值的高低关系同入库泥沙量正好相反,遵循"随地表林地和草地面积比例的增加,保沙价值增加"的规律。随产沙总量的增加,高产沙强度像元呈现从水库周边逐渐向中上游蔓延的趋势。2)退耕还林政策单纯以坡度作为指标,指导土地覆被的转化,对集水区减轻水环境磷素非点源污染功效较差。除了全为未利用地覆被的情景10,余下9类情景模拟的入库磷素量及过滤磷素经济价值的高低关系完全一致,呈农田草地林地的规律。随入库磷素总量的增加,高强度磷素输出像元从雅砻江流域源区和大河湾区,逐渐蔓延扩散至集水区整个水网。3)随着集水区地表林地覆盖面积比例的减少,集水区生态系统总发电净利润值增加,且高净利润像元呈现从冕宁和喜德县的东部逐渐向整个集水区东南部乃至整个下游蔓延的趋势。4)从减轻对环境的负效应以及提升利益相关方福祉的角度,以坡度6°上下划分林地和耕地的情景5和以坡度15°和6°为阈值划分林草农的情景3为除极端的情景外,综合指标提升最高的两种情景。     

Helicobacter pylori Genotypes Associated with Gastric Histo-Pathological Damages in a Moroccan Population

H. pylori persistent infection induces chronic gastritis and is associated with peptic ulcer disease and gastric carcinoma development. The severity of these diseases is related to human’s genetic diversity, H. pylori genetic variability and environmental factors. To identify the prevalence of histo-pathological damages caused by H. pylori infection in Moroccan population, and to determine their association to H. pylori genotypes, a prospective study has been conducted during 3 years on patients attending the gastroenterology department of Hassan II University Hospital (CHU) of Fez, Morocco. A total of 801 Moroccan adults’ patients were recruited; H. pylori was diagnosed and genotyped by PCR in biopsy specimens and histological exam was performed. We found a high rate of glandular atrophy. Chronic inflammation, neutrophil activity and glandular atrophy showed statistically significant association with H. pylori infection. However, intestinal metaplasia was inversely associated to this infection and no association was observed with gastric cancer cases. A statistically significant association was found between intestinal metaplasia and vacAs1 and vac Am1 genotypes in patients aged 50 years and more but not in younger. This last genotype is also associated to gastric cancer. In this study, gastric cancer showed no significant association with H. pylori. Further studies are warranted to determine the role of other etiological agents such as Epstein-Barr virus, human papillomavirus and possibly environmental and dietetic factors in the occurrence of this pathology.     

Human eosinophils exert TNF-α and granzyme A-mediated tumoricidal activity toward colon carcinoma cells

Peripheral blood and tissue eosinophilia is a prominent feature in allergic diseases and helminth infections. In cancer patients, tumor-associated tissue eosinophilia is frequently observed. Tumor-associated tissue eosinophilia can be associated with a favorable prognosis, notably in colorectal carcinoma. However, underlying mechanisms of eosinophil contribution to antitumor responses are poorly understood. We have in this study investigated the direct interactions of human eosinophils with Colo-205, a colorectal carcinoma cell line, and show that eosinophils induce apoptosis and directly kill tumor cells. Using blocking Abs, we found that CD11a/CD18 complex is involved in the tumoricidal activity. Coculture of eosinophils with Colo-205 led to the release of eosinophil cationic protein and eosinophil-derived neurotoxin as well as TNF-α secretion. Moreover, eosinophils expressed granzyme A, which was released upon interaction with Colo-205, whereas cytotoxicity was partially inhibited by FUT-175, an inhibitor of trypsin-like enzymatic activity. Our data present the first demonstration, to our knowledge, that granzyme A is a cytotoxic mediator of the eosinophil protein arsenal, exerting eosinophil tumoricidal activity toward Colo-205, and provide mechanistic evidence for innate responses of eosinophil against tumor cells.     

Inhibition of K+ efflux prevents mitochondrial dysfunction, and suppresses caspase-3-, apoptosis-inducing factor-, and endonuclease G-mediated constitutive apoptosis in human neutrophils

Neutrophils die rapidly via apoptosis and their survival is contingent upon rescue from constitutive programmed cell death by signals from the microenvironment. In these experiments, we investigated whether prevention of K⁺ efflux could affect the apoptotic machinery in human neutrophils. Disruption of the natural K⁺ electrochemical gradient suppressed neutrophil apoptosis (assessed by annexin V binding, nuclear DNA content and nucleosomal DNA fragmentation) and prolonged cell survival within 24–48 h of culture. High extracellular K⁺ (10–100 mM) did not activate extracellular signal-regulated kinase (ERK) and Akt, nor affected phosphorylation of p38 MAPK associated with constitutive apoptosis. Consistently, pharmacological blockade of ERK kinase or phosphatidylinositol 3-kinase (PI 3-kinase) did not affect the anti-apoptotic action of KCl. Inhibition of K⁺ efflux effectively reduced, though never completely inhibited, decreases in mitochondrial transmembrane potential (ΔΨ_m) that preceded development of apoptotic morphology. Changes in ΔΨ_m resulted in attenuation of cytochrome c release from mitochondria into the cytosol and decreases in caspase-3 activity. Culture of neutrophils in medium containing 80 mM KCl with the pan-caspase inhibitor Z-VAD-FMK resulted in slightly greater suppression of apoptosis than KCl alone. High extracellular KCl also attenuated translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) from mitochondria to nuclei. The DNase inhibitor, aurintricarboxylic acid (ATA) partially inhibited nucleosomal DNA fragmentation, and the effects of ATA and 80 mM KCl were not additive. These results show that prevention of K⁺ efflux promotes neutrophil survival by suppressing apoptosis through preventing mitochondrial dysfunction and release of the pro-apoptotic proteins cytochrome c, AIF and EndoG independent of ERK, PI 3-kinase and p38 MAPK. Thus, K⁺ released locally from damaged cells may function as a survival signal for neutrophils.     

The modalities of the sexual cycle of Octopus vulgaris in the southern Moroccan Atlantic (Tantan, Boujdour)

The reproduction of Octopus vulgaris between Tan Tan and Boujdour is studied. The samples used are sorted monthly from commercial catches of coastal trawlers operating in this area from December 2001 to May 2003. The study shows that sexual maturity is in advance for males than for females. Two spawning periods are made out by the follow-up of the RGS: a spring period from March to July, and an autumnal period, which is less intense, between September and October. The division of spermatogonia and spermatocytes reaches its maximal intensity in July and December, whereas the spermiogenesis is active until the time of mating. The vitellogenesis starts in mid-December and extends until the following spawning period. This reveals a later gonadic development for females than for males; approximately seven months for females and three months for males.     

Distribution et écologie des associations d’ostracodes récents de l’estuaire de Tahadart (Maroc Nord-Occidental)

Forty-five ostracod species were identified for the first time in the Tahadart estuary (NW Morocco). They can be grouped into five different ecological assemblages, which characterise four estuarine ecozones. A first ecozone occurs in temporary waters located between the tidal channels of the inner estuary and it is characterised by ostracod species typical of fresh to brackish waters. In the main estuary area, the ostracod fauna is dominated by clearly euryhaline species that account for nearly 70% of the entire fauna. The relative abundance of the different assemblages allows us to subdivide the estuarine environment along a longitudinal profile into mouth, outer and inner estuary. The estuary's mouth displays the highest values of marine euhaline, phytal and periphytal as well as ubiquitous species and the lowest values of very euryhaline species; the latter are the only species present in the inner estuary. The outer estuary exhibits intermediate percentages of the different ecological assemblages. This distribution, characterized by the absence of limnic species, points to the influence of marine waters in an open estuary with a low fresh water input. In the estuary's mouth, as well as in the outer estuary, where the slikke and schorre are well developed, the distance to the emersion line is underlined by the lower occurrence of marine and ubiquitous species and the higher occurrence of the very euryhaline ones. The Tahadart estuary displays a moderate to high ostracod diversity with distinct differences among the ecological zones. The stress of this environment is highlighted by the low diversity characteristics of extreme environments, alike in the inner estuary and in some areas located far from the emersion level. The relative position with respect to the emersion line, as well as the presence of gross detritic sediments and vegetation, appear to be of importance for the good development of the ostracods.