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81.
There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1H)-one and 3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC50 range is 2.1 − 9.8 µM), comparing to sorafenib (IC50 = 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC50 range is 2.9 − 5.4 µM), comparing to sorafenib (IC50 = 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib).  相似文献   
82.
Diabetes mellitus induces testicular damage, increases sperm abnormalities, and impairs reproductive dysfunction due to induction of endocrine disturbance and testicular oxidative stress. This study evaluated the reproductive protective effect of ellagic acid (EA) against testicular damage and abnormalities in sperm parameters in Streptozotocin (STZ)-induced diabetic rats (T1DM) and examined some possible mechanisms of protection. Adult male rats were segregated into 5 groups (n = 12 rat/each) as control, control + EA (50 mg/kg/day), T1DM, T1DM + EA, and T1DM + EA + brusatol (an Nrf-2 inhibitor) (2 mg/twice/week). All treatments were conducted for 12 weeks, daily. EA preserved the structure of the seminiferous tubules, prevented the reduction in sperm count, motility, and viability, reduced sperm abnormalities, and downregulated testicular levels of cleaved caspase-3 and Bax in diabetic rats. In the control and diabetic rats, EA significantly increased the circulatory levels of testosterone, reduced serum levels of FSH and LH, and upregulated Bcl-2 and all steroidogenic genes (StAr, 3β-HSD1, and 11β-HSD1). Besides, it reduced levels of ROS and MDA but increased levels of GSH and MnSOD and the transactivation of Nrf2. All these biochemical alterations induced by EA were associated with increased activity and nuclear accumulation of Nrf2. However, all these effects afforded by EA were weakened in the presence of brusatol. In conclusion, EA could be an effective therapy to alleviated DM-induced reproductive toxicity and dysfunction in rats by a potent antioxidant potential mediated by the upregulation of Nrf2.  相似文献   
83.
84.
A study was undertaken to investigate the presence of archaeal diversity in saltpan sediments of Goa, India by 16S rDNA-dependent molecular phylogeny. Small subunit rRNA (16S rDNA) from saltpan sediment metagenome were amplified by polymerase chain reaction (PCR) using primers specific to the domain archaea. 10 unique phylotypes were obtained by PCR based RFLP of 16S rRNA genes using endonuclease Msp 1, which was most suitable to score the genetic diversity. These phylotypes spanned a wide range within the domain archaea including both crenarchaeota and euryarcheaota. None of the retrieved crenarchaeota sequences could be grouped with previously cultured crenarchaeota however; two sequences were related with haloarchaea. Most of the sequences determined were closely related to the sequences that had been previously obtained from metagenome of a variety of marine environments. The phylogenetic study of a site investigated for the first time revealed the presence of low archaeal population but showed yet unclassified species, may specially adapted to the salt pan sediment of Goa.  相似文献   
85.
86.
AimsLigands for the vitamin D receptor (VDR) regulate apolipoprotein A-I (apo A-I) gene expression in a tissue-specific manner. The vitamin D metabolite 24, 25-dihydroxycholecalciferol (24, 25-(OH)2D3) has been shown to possess unique biological effects. To determine if 24, 25-(OH)2D3 modulates apo A-I gene expression, HepG2 hepatocytes and Caco-2 intestinal cells were treated with 24, 25-(OH)2D3 or its precursor 25-OHD3.Main methodsApo A-I protein levels and mRNA levels were measured by Western and Northern blotting, respectively. Changes in apo A-I promoter activity were measured using the chlorampenicol acetytransferase assay.Key findingsTreatment with 24, 25-(OH)2D3, but not 25-OHD3, inhibited apo A-I secretion in HepG2 and Caco-2 cells and apo A-I mRNA levels and apo A-I promoter activity in HepG2 cells. To determine if 24, 25-(OH)2D3 represses apo A-I gene expression through site A, the nuclear receptor binding element that is essential for VDRs effects on apo A-I gene expression, HepG2 cells were transfected with plasmids containing or lacking site A. While the site A-containing plasmid was suppressed by 24, 25-(OH)2D3, the plasmid lacking site A was not. Likewise, treatment with 24, 25-(OH)2D3 suppressed reporter gene expression in cells transfected with a plasmid containing site A in front of a heterologous promoter. Finally, antisense-mediated VDR depletion failed to reverse the silencing effects of 24, 25-(OH)2D3 on apo A-I expression.SignificanceThese results suggest that the vitamin D metabolite 24, 25-(OH)2D3 is an endogenous regulator of apo A-I synthesis through a VDR-independent signaling mechanism.  相似文献   
87.
Motility and chemotaxis are essential components of pathogenesis for many infectious bacteria, including Borrelia burgdorferi, the causative agent of Lyme disease. Motility and chemotaxis genes comprise 5 to 6% of the genome of B. burgdorferi, yet the functions of most of those genes remain uncharacterized, mainly due to the paucity of a nonpolar gene inactivation system. In this communication, we describe the development of a novel gene inactivation methodology to target B. burgdorferi fliL, a putative periplasmic flagellar gene located in a large motility operon and transcribed by RNA polymerase containing σ(70). Although the morphology of nonpolar fliL mutant cells was indistinguishable from that of wild-type cells, the mutant exhibited a defective-motility phenotype. Cryo-electron tomography (cryo-ET) of intact organisms revealed that the periplasmic flagella in the fliL mutant were frequently tilted toward the cell pole instead of their normal orientation toward the cell body. These defects were corrected when the mutant was complemented in cis. Moreover, a comparative analysis of flagellar motors from the wild type and the mutant provides the first structural evidence that FliL is localized between the stator and rotor. Our results suggest that FliL is likely involved in coordinating or regulating the orientation of periplasmic flagella in B. burgdorferi.  相似文献   
88.
The organophosphate pesticide chlorpyrifos (CP) has been used extensively since the 1960s for insect control. However, its toxic effects on mammals and persistence in environment necessitate its removal from contaminated sites, biodegradation studies of CP-degrading microbes are therefore of immense importance. Samples from a Pakistani agricultural soil with an extensive history of CP application were used to prepare enrichment cultures using CP as sole carbon source for bacterial community analysis and isolation of CP metabolizing bacteria. Bacterial community analysis (denaturing gradient gel electrophoresis) revealed that the dominant genera enriched under these conditions were Pseudomonas, Acinetobacter and Stenotrophomonas, along with lower numbers of Sphingomonas, Agrobacterium and Burkholderia. Furthermore, it revealed that members of Bacteroidetes, Firmicutes, α- and γ-Proteobacteria and Actinobacteria were present at initial steps of enrichment whereas β-Proteobacteria appeared in later steps and only Proteobacteria were selected by enrichment culturing. However, when CP-degrading strains were isolated from this enrichment culture, the most active organisms were strains of Acinetobacter calcoaceticus, Pseudomonas mendocina and Pseudomonas aeruginosa. These strains degraded 6–7.4 mg L?1 day?1 of CP when cultivated in mineral medium, while the consortium of all four strains degraded 9.2 mg L?1 day?1 of CP (100 mg L?1). Addition of glucose as an additional C source increased the degradation capacity by 8–14 %. After inoculation of contaminated soil with CP (200 mg kg?1) disappearance rates were 3.83–4.30 mg kg?1 day?1 for individual strains and 4.76 mg kg?1 day?1 for the consortium. These results indicate that these organisms are involved in the degradation of CP in soil and represent valuable candidates for in situ bioremediation of contaminated soils and waters.  相似文献   
89.
The presence of plasmonic Fano-like resonances in the optical response of isolated and dimer metal-dielectric-metal nanostructures are investigated theoretically. The nanostructures are engineered in such a way to support multiple Fano-like resonances that are induced by the interference of bright and dark plasmon modes. It is found that the dimer resonators exhibit different types of Fano resonances for both the transverse and longitudinal polarizations unlike conventional nanodimers. Several configurations of the dimer Fano resonator are analyzed with special emphasis on the Fano spectral line shape. Breaking the symmetry of the dimer nanostructure in various directions control the asymmetric line shape and provides different kinds of unique Fano resonances. In certain cases, the Fano resonators exhibit multiple Fano resonances that are particularly significant for plasmon line shaping and can serve as platforms for multi-wavelength sensing applications.  相似文献   
90.
The amount of quantitative genetic variation within an invasive species influences its ability to adapt to conditions in the new range and its long-term persistence. Consequently, this aspect of genetic diversity (or evolutionary potential) can be a key factor in the success of species invasions. Previous studies have compared the evolutionary potential of populations in introduced versus native ranges of invasive species, but to date no study has examined differences among introduced-range populations of such species in levels of quantitative genetic variation expressed in ecologically relevant environments. We assessed quantitative variation of fitness, life-history, and functional traits in six geographically separate introduced-range populations of the invasive annual Polygonum cespitosum, by comparing norms of reaction for a large sample of genotypes (16–19 per population) expressed in response to two glasshouse environments simulating contrasting habitats in this new range. Patterns of reaction norm diversity varied considerably among the 6 populations studied. Two populations showed very little quantitative genetic variation in both environments. In contrast, two other populations contained significant genetic variation for fitness and life-history traits in the form of genotypes with low performance in both habitats. Finally, two populations showed significant norm of reaction diversity in the form of cross-over interaction: genotypes that performed relatively well in one environment did poorly in the other. Differences among populations in potential selective response are likely to affect the dynamics and future spread of P. cespitosum, since specific populations will likely contribute differently to the invasion process. More generally, our results suggest that the evolutionary component of long-term invasion success may depend on population rather than on species-level processes.  相似文献   
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