4-(4-(Methylsulfonyl)phenyl)-3-phenoxy-1-phenylazetidin-2-one: a novel COX-2 inhibitor acting selectively and directly on cancerous B-lymphocyte mitochondria

A new series of 3-phenoxyazetidin-2-ones (β-lactams) were designed and synthesized for the evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In this study, the effects of a synthetic of β-lactam-structured COX-2 inhibitor with 4-(4-(methylsulfonyl)phenyl)-3-phenoxy-1-phenylazetidin-2-one on cell viability of cancerous lymphoblast isolated from patients diagnosed with acute lymphocytic leukemia (ALL) and normal lymphocytes collected from healthy donors were investigated. The viability % of cancer lymphoblast and normal lymphocyte treated 4-(4-(methylsulfonyl)phenyl)-3-phenoxy-1-phenylazetidin-2-one were tested with MTT assay. Apoptosis and necrosis were measured by double stains of annexin V and propidium iodide, and caspase-3 as a final mediator in apoptotic death measured by colorimetric assay. Mitochondria were isolated from both cancerous lymphoblast and normal lymphocytes to measure parameters of mitochondrial damage such as reactive oxygen species (ROS) formation, mitochondrial membrane potential decrease, swelling, and cytochrome c release following the administration of azithidine-2-one derivative, 4-(4-(methylsulfonyl)phenyl)-3-phenoxy-1-phenylazetidin-2-one. Our results showed that 4-(4-(methylsulfonyl)phenyl)-3-phenoxy-1-phenylazetidin-2-one inhibited proliferation of cancerous lymphoblast in a concentration-dependent manner by inducing apoptosis but not in normal lymphocytes. Treatment with azithidine-2-one derivative produced a rapid loss of mitochondrial transmembrane potential, stimulation of release of ROS and mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. Data suggest that 4-(4-(methylsulfonyl)phenyl)-3-phenoxy-1-phenylazetidin-2-one-induced ROS production led to mitochondria-mediated death signaling that resulted in apoptosis in cancerous lymphoblast cells. The induction of apoptosis by azithidine-2-one compounds, such as 4-(4-(methylsulfonyl)phenyl)-3-phenoxy-1-phenylazetidin-2-one, may provide a mechanism for its cancer chemopreventive action in acute lymphocytic leukemia cells.     

Digit ratio (2D:4D) and dominance rank in female rhesus macaques (Macaca mulatta)

Female rhesus macaques exhibit matrilineal dominance structures, and high dominance rank confers fitness benefits across a lifetime and across generations. Rank effects are “inherited” through social processes that are well understood; however, biological mechanisms that might impact these processes are not well known. Recently, it has been shown that prenatal androgens appear to be implicated in supporting dominance rank hierarchies in some mammals. In humans, interindividual differences in the second (index) to fourth (ring) digit ratio (2D:4D) have been linked indirectly to variation in prenatal androgens, with low 2D:4D in both sexes associated with higher inferred prenatal androgen effects. 2D:4D has also been related to dominant social behavior and has been shown to co-vary with social systems across nonhuman primate species. Here, we investigate how 2D:4D co-varies with socially inherited dominance rank in female rhesus macaques. Low 2D:4D was associated with higher-ranking females, while higher 2D:4D was associated with lower-ranking females. Similar relationships were also shown between ranked families within matrilines. This is the first study to show such a relationship between 2D:4D and dominance rank in a nonhuman primate and suggests that prenatal androgen effects could be involved in the maintenance of dominance rank in female cercopithecine primates.     

六溴环十二烷(HBCD)对H4细胞和SK-N-AS细胞脱碘酶2和3表达的影响

六溴环十二烷(hexabromocyclododecane,HBCD)与多溴联苯醚(polybrominated diethyl ethers,PBDEs)复合污染体系,对人类健康尤其神经系统所造成的潜在危害及其机制一直是笔者课题组的研究方向。HBCD是广泛使用的溴化阻燃剂,与PBDEs一样,会通过干扰内分泌系统、影响甲状腺激素分泌及损伤神经系统,对生物体产生发育神经毒性。作为系列研究之一,本研究以H4人脑神经胶质瘤细胞和SK-N-AS人神经母细胞瘤细胞为体外生物模型,通过观察HBCD对H4细胞Ⅱ型脱碘酶(Dio2)和SK-N-AS细胞Ⅲ型脱碘酶(Dio3)表达的调控,初步探讨了HBCD对神经系统局部甲状腺激素水平的潜在影响。H4细胞和SK-N-AS细胞分别暴露于0、1、3和9μmol·L-1HBCD 24 h后,采用MTT法检测细胞活力,Western Blot和RT-PCR法分别分析Dio2和Dio3蛋白和基因的表达,酶联免疫吸附测定(ELISA)法检测H4细胞脑源性神经细胞营养因子(BDNF)的分泌。结果表明,HBCD以剂量依赖方式降低H4细胞和SK-N-AS细胞生存率,引起H4细胞Dio2蛋白和基因表达下调,而致SK-N-AS细胞Dio3蛋白和基因表达上调。此外,HBCD还降低H4细胞BDNF的分泌。这表明,HBCD很可能通过影响神经和胶质细胞脱碘酶的表达,影响脑局部甲状腺激素水平,从而引起神经系统损伤及发育神经毒性。     

Modelling seasonal dynamics of biomasses and nitrogen contents in a seagrass meadow (Zostera noltii Hornem.): application to the Thau lagoon (French Mediterranean coast)

Anumerical deterministic model for a seagrass ecosystem (Zostera noltii meadows) has been developed for the Thau lagoon. It involves both above- and belowground seagrass biomasses, nitrogen quotas and epiphytes. Driving variables are light intensity, wind speed, rain data and water temperature. This seagrass model has been coupled to another biological model in order to simulate the relative contributions of each primary producer to: (i) the total ecosystem production, (ii) the impact on inorganic nitrogen and (iii) the fluxes towards the detritus compartment. As a first step in the modelling of seagrass beds in the Thau lagoon, the model has a vertical structure based on four boxes (a water box on top of three sediment boxes) and the horizontal variability is neglected until now. This simple box structure is nevertheless representative for the shallow depth Z. noltii meadows, spread over large areas at the lagoon periphery.After calibration, simulation results have been compared with in situ measurements and have shown that the model is able to reproduce the general pattern of biomasses and nitrogen contents seasonal dynamics. Moreover, results show that, in such shallow ecosystems, seagrasses remain the most productive compartment when compared with epiphytes or phytoplankton productions, and that seagrasses, probably due to their ability in taking nutrients in the sediment, have a lower impact on nutrient concentration in the water column than the phytoplankton. Furthermore, in spite of active mechanisms of internal nitrogen redistribution and reclamation, the occurrence of a nitrogen limitation of the seagrass growth during summer, already mentioned in the literature, have also been pointed out by the model. Finally, simulations seems to point out that epiphytes and phytoplankton could compete for nitrogen in the water column, while a competition for light resources seems to be more likely between epiphytes and seagrasses.     

Digit length ratio (2D/4D): comparing measurements from X-rays and photographs in field voles (<Emphasis Type="Italic">Microtus agrestis</Emphasis>)

The ratio of second-to-fourth digit length (2D/4D) has been suggested to be a useful adult age marker of intrauterine exposure to steroids because it should be sexually dimorphic and fixed already in utero. Numerous studies mainly on humans have supported this conclusion, but it is yet unclear how well this applies to other vertebrates. This information would be especially valuable to field biologists to whom measuring steroids in utero is often impossible. The non-human studies conducted so far have yielded inconsistent results, perhaps due to the variety of different methods employed in measuring 2D/4D. We examined the age and sex dependency and lateral asymmetry of 2D/4D in field voles (Microtus agrestis) and compared whether these effects differed between 2D/4D measurements taken from photographs and X-rays. Our results show that 2D/4D measurements from photos had a higher measurement error and gave consistently higher 2D/4D than those from X-rays. According to both measurement methods, the right paw showed higher 2D/4D values than the left paw (lateral asymmetry). Adult voles had a lower 2D/4D than juveniles when measured from X-rays, but not when measured from photographs. We found no evidence for a sex difference in 2D/4D using either of the measurement methods. Our findings thus suggest that X-rays, due to their greater accuracy, should be preferred over photographs for measuring digit ratios in rodents. Our results also indicate that in this species, 2D/4D is laterally asymmetric, but it may not be either fixed in utero or sexually dimorphic. In conclusion, 2D/4D appears to be a rather species- and method-specific measure and researchers should be careful when generalising its applicability to study early hormonal effects in vertebrates.     

Variation in protein patterns within and among polychaete sibling species of the genus<Emphasis Type="Italic"> Marenzelleria</Emphasis> (Spionidae): a preliminary survey

Differences in protein patterns of the soluble protein fraction among the sibling species Marenzelleria viridis (formerly type I) and M. neglecta (formerly type II) were investigated under common environmental conditions using two-dimensional gel electrophoresis (2D-PAGE). Protein expression was determined using general protein staining with Coomassie-blue and compared with radioactive labeling of proteins. In the well-resolved region of stained gels an average of 319 protein spots for M. viridis and 241 spots for M. neglecta could be detected. High sensitivity of radiolabeling allowed separation of an average of 517 and 496 spots for M. viridis and for M. neglecta, respectively. Differences in protein expression between both species could be attributed mainly to qualitative differences in protein patterns. Triplet pattern was used to calculate the genetic similarity of the two species. Thus, 373 protein spots were scored for this analysis; whereas 304 spots were invariant, 36 spots were specific for M. viridis, while 33 spots were specific for M. neglecta. The genetic similarity (F) of the two Marenzelleria sibling species was 0.815. Apart from presence and absence, differences between both species resulted either from slight changes in the isoelectric point or from molecular weight, but rarely from both. Genetic variability was found only among specimens of M. viridis. The experimental conditions to perform two-dimensional electrophoresis for these polychaete species were established for subsequent investigations on a proteomic level. Using 2D-PAGE we expect further insight into the evolutionary adaptation in Marenzelleria spp.Communicated by O. Kinne, Oldendorf/Luhe     

Interaction between cadmium,lead and potassium fertilizer (K<Subscript>2</Subscript>SO<Subscript>4</Subscript>) in a soil-plant system

A pot experiment was conducted to examine the influence of potassium (K) fertilizer (K₂SO₄) application on the phytoavailability and speciation distribution of cadmium (Cd) and lead (Pb) in soil. Spring wheat (Triticum aestivum L.) was selected as the test plant. There were seven treatments including single and combined contamination of Cd and Pb. CdCl₂·2.5 H₂O and Pb(NO₃)₂ were added to the soil at the following dosages: Cd + Pb = 0.00 + 0.00, 5.00 + 0.00, 25.0 + 0.00, 0.00 + 500, 0.00 + 1000, 5.00 + 500 and 25.0 + 1000 mg kg⁻¹, denoted by CK, T1, T2, T3, T4, T5 and T6, respectively. The K fertilizer had five levels: 0.00, 50.0, 100, 200 and 400 mg K₂O kg⁻¹ soil, denoted by K0, K1, K2, K3 and K4, respectively. The results showed that the K fertilizer promoted the dry weight (DW) of wheat in all treatments and alleviated the contamination by Cd and Pb. The application of K₂SO₄ reduced the uptake of Cd in different parts including roots, haulms and grains of wheat; the optimum dosage was the K2 level. K supply resulted in a significant (P < 0.05) decrease in the soluble plus exchangeable (SE) fraction of Cd and there was a negative correlation (not significant, P > 0.05) between the levels of K and the SE fraction of Cd in soil. The application of the K fertilizer could obviously restrain the uptake of Pb by wheat and there were significant (P < 0.05) negative correlations between the concentrations of Pb in grains and the levels of K in soil. K supply resulted in a decrease in the SE fraction of Pb (except the K1 level) from the K0 to K4 levels. At the same time, the application of the K fertilizer induced a significant (P < 0.05) decrease in the weakly specifically adsorbed (WSA) fraction of Pb and a significant (P < 0.05) increase in the bound to Fe–Mn oxides (OX) fraction of Pb. At different K levels, the concentration of Pb in the roots, haulms and grains had a positive correlation with the SE (not significant, P > 0.05) and WSA (significant, P < 0.05) fractions of Pb in the soil. All the K application levels in this experiment reduced the phytoavailability of Cd and Pb. Thus, it is feasible to apply K fertilizer (K₂SO₄) to alleviate contamination by Cd and/or Pb in soil. Moreover, the level of K application should be considered to obtain an optimal effect with the minimum dosage.     

Risk-based prediction of metal toxicity in sediment and impact on human health due to consumption of seafood (Saccostrea cucullata) found in two highly industrialised coastal estuarine regions of Eastern India: a food safety issue

Estuarine ecosystems of the Bay of Bengal, India, are considered as the most productive environment, which have been persistently threatened by substantial anthropogenic activity. This study aims to investigate the metal contamination in the sediment of two estuaries and possible biomagnifications in the indigenous edible oyster Saccostrea cucullata and related health hazards due to its consumption. The accumulative ecological risks indicated that the sediment is moderate to strongly contaminated with cadmium and lead. The sediment pollution index and pollution load index suggested that the sediment possesses a little ecological stress on the exposed flora and fauna. The statistical interpretation highlights the most metals which have a similar source of origin and are bound to the finer fractions of the sediment, except nickel. Bioaccumulation of sediment-associated Cu and Zn in oyster reflects their potential biomagnifications through aquatic food chain. HPI range was below the critical limit of safe human consumption. The non-carcinogenic (THQ) and carcinogenic (CR) health hazards were estimated from the PTDI provided by USEPA. Except Cr, Hg and Zn, the THQ of all other metals was > 1 suggesting detrimental non-carcinogenic health effects on humans. The TCR of Cr and Cd above safety limit indicates the exposed population might be under severe carcinogenic threat due to those metals.

     

Using a biogeochemistry model in simulating forests productivity responses to climatic change and [CO2] increase: example of Pinus halepensis in Provence (south-east France)

Tree-ring chronologies provide long-term records of growth in natural environmental conditions and may be used to evaluate the impacts of climatic change and [CO₂] increase on forest productivity. This study focuses on 21 Pinus halepensis forest stands in calcareous Provence (in the south-east France). Changes in productivity are simulated using the global biogeochemistry model BIOME3, that we have adapted to run with chronological data. Tree-ring data (width and density) were used to estimate, for each stand, an observed series of changes in productivity. Simulated and observed productivity changes are then compared to validate the chronological biogeochemistry model BIOME3C. Variations in productivity were well reconstructed at 15 sites. After this validation, BIOME3C was used to simulate forest productivity changes for a 2×CO₂ scenario. The 2×CO₂ climate used as input was obtained using results from Météo-France’s ARPEGE atmospheric general circulation model (AGCM), downscaled to local meteorological stations. Productivity increases moderately for all stands (from 17 to 24%) when climatic changes alone were taken into account. The main factor responsible for this increase is a reduction in summer drought severity. Productivity increases highly for all stands (from 72 to 86%) when the physiological fertilising effect of the [CO₂] increase is considered separately. When both climatic changes and the [CO₂] increase were taken into account, productivity increases highly, from 107% (for Moustier) to 141% (for La Ciotat). The direct fertilising effect of [CO₂] increase has a greater influence on the forest stands productivity than the indirect climatic changes effect. These results also exhibit the importance of the synergy between the effects of climate change and [CO₂] increase, as the increase in productivity resulting from the combined effects are more than the sum of the individual CO₂ and climate effects. Although the detected effects of global change during the 20th century were slight, acceleration of these changes is likely to lead to great changes in the future productivity of P. halepensis forests.     

Optimization of denitrifying phosphorus removal in a pre-denitrification anaerobic/anoxic/post-aeration + nitrification sequence batch reactor (pre-A<Subscript>2</Subscript>NSBR) system: Nitrate recycling,carbon/nitrogen ratio and carbon source type

Because the efficiency of biological nutrient removal is always limited by the deficient carbon source for the low carbon/nitrogen (C/N) ratio in real domestic sewage, the denitrifying phosphorus removal (DNPR) was developed as a simple and efficient method to remove nitrogen and phosphorous. In addition, this method has the advantage of saving aeration energy while reducing the sludge production. In this context, a pre-denitrification anaerobic/anoxic/post-aeration + nitrification sequence batch reactor (pre-A₂NSBR) system, which could also reduce high ammonia effluent concentration in the traditional two-sludge DNPR process, is proposed in this work. The pre-A₂NSBR process was mainly composed of a DNPR SBR and a nitrifying SBR, operating as alternating anaerobic/anoxic/post-aeration + nitrification sequence. Herein, the long-term performance of different nitrate recycling ratios (0–300%) and C/N ratios (2.5–8.8), carbon source type, and functional microbial community were studied. The results showed that the removal efficiency of total inorganic nitrogen (TIN, including NH₄⁺-N, NO₂^– -N, and NO₃^– -N) gradually increased with the nitrate recycling ratios, and the system reached the highest DNPR efficiency of 94.45% at the nitrate recycling ratio of 300%. The optimum C/N ratio was around 3.9–7.3 with a nitrogen and phosphorus removal efficiency of 80.15% and 93.57%, respectively. The acetate was proved to be a high-quality carbon source for DNPR process. The results of fluorescence in situ hybridization (FISH) analysis indicated that nitrifiers and phosphorus accumulating organisms (PAOs) were accumulated with a proportion of 19.41% and 26.48%, respectively.

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