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141.
A series of novel podophyllotoxin derivatives containing structural modifications at C-4 (7-14), C-4' (16-17), and the methylenedioxy A-ring (23-28) was synthesized and tested for inhibition of HIV replication. Four of these compounds (25-28) were previously reported to show EC(50) values of <0.001 microg/mL and therapeutic index (TI) values >120. Three of the newly tested compounds (8, 12, and 20) showed good activity with EC(50) values of 0.012, <0.001, and 0.389 microg/mL and TI values of 19.1, >16, and 19.4, respectively. A comparison of the anti-HIV activity of these derivatives suggested that an opened A-ring with 6,7-dimethoxy substitution and a 4'-demethylated E ring enhanced anti-HIV activity. 相似文献
142.
Cosentino U Varí MR Saracino AA Pitea D Moro G Salmona M 《Journal of molecular modeling》2005,11(1):17-25
Tetracycline (TC) and its derivatives have recently been proposed as a new class of antagonists in prion diseases as they prevent the aggregation of prion protein peptides and their acquisition of protease resistance in vitro and in vivo. Looking for relationships between conformational flexibility and biological activity, we searched for a geometrical pharmacophore by investigating, in aqueous solution, the conformational behavior of 15 TCs in both the zwitterionic and the anionic forms. For TC similar conformational flexibility was found for the two forms and two main conformational families were detected, an extended and a folded conformation characterized by different intramolecular hydrogen-bond networks. On comparing the Molecular Mechanics results with the ab initio ones and the experimental evidence, it can be seen that the conformational behavior of TC is reasonably well predicted by the MM2 force field, whereas the conformational energies provided by the Amber force field are unreliable. The conformational analysis of the other TC derivatives was then performed by the MM2 force field. As a result, their conformational behavior was similar to that observed for TC itself. Despite the hydronaphthacene moiety's conformational flexibility, no geometrical pharmacophore was found among the TCs, i.e. properties other than geometrical ones should play a crucial role in determining their anti-fibrillogenic ability. 相似文献
143.
Yonekawa H; Moriwaki K; Gotoh O; Miyashita N; Matsushima Y; Shi LM; Cho WS; Zhen XL; Tagashira Y 《Molecular biology and evolution》1988,5(1):63-78
The Japanese mouse, Mus musculus molossinus, has long been considered an
independent subspecies of the house mouse. A survey of restriction- site
haplotypes of mitochondrial DNA (mtDNA) showed that Japanese mice have two
main maternal lineages. The most common haplotype is closely related to the
mtDNA of the European subspecies M. m. musculus. The other common haplotype
and two minor ones are closely related to each other and to the mtDNA of an
Asiatic subspecies, M. m. castaneus. Two other rare variants are probably
the result of recent contamination by European M. m. domesticus. The
musculus type of mtDNA is found in the southern two-thirds of Japan,
whereas the common castaneus type is found in the northern third and the
minor variants are found sporadically throughout Japan. The castaneus mtDNA
lineage had a few minor variants, whereas the musculus lineage was
completely monomorphic. By contrast, the native population of M. m.
castaneus and the Chinese and Korean musculus populations were highly
polymorphic. These results suggest that M. m. molossinus is a hybrid
between ancestral colonies, possibly very small, of M. m. musculus and M.
m. castaneus, rather than an independent subspecies.
相似文献
144.
Background
Dopamine (DA) may be involved in central obesity (CO), an inflammatory condition, through its role in the central nervous system and in periphery, where it may affect immune cell function through five different DA receptors (DR). Whether dopaminergic pathways in peripheral immune cells are implicated in the inflammatory condition linked to CO is however unknown.Methods
In a cohort of blood donors with and without CO, categorized by waist circumference (WC) (CO: WC ≥0.80 m in women and ≥0.94 m in men), we studied the expression of DR and tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA, in peripheral blood mononuclear cells (PBMCs) and their relation with anthropometric and metabolic/endocrine and inflammatory parameters. DR D1-5 and TH expression was assessed by semi quantitative real-time PCR. As inflammatory markers we investigated the immunophenotype of monocyte subsets by flow cytometry, staining for CD14, CD16, CD11b and CD36.Results
CO individuals showed higher plasma levels of leptin and higher inflammatory pattern of monocytes compared with non-CO. PBMC expression of DR D2, DR D4 and DR D5 as well as of TH were lower in CO in comparison with non-CO. DR D2, and DR D5 expression correlated with lower WC and weight, and with lower inflammatory pattern of monocytes, and TH expression correlated with lower WC. DR D4 expression correlated with lower plasma levels of glycosylated hemoglobin, and DR D2 expression correlated with lower CO.Conclusions
Results show that CO is associated with peripheral inflammation and downregulation of dopaminergic pathways in PBMCs, possibly suggesting DR expressed on immune cells as pharmacological targets in obesity for better metabolic outcome. 相似文献145.
Raquel Salvador‐Gallego Markus Mund Katia Cosentino Jale Schneider Joseph Unsay Ulrich Schraermeyer Johann Engelhardt Jonas Ries Ana J García‐Sáez 《The EMBO journal》2016,35(4):389-401
Bax is a key regulator of apoptosis that, under cell stress, accumulates at mitochondria, where it oligomerizes to mediate the permeabilization of the mitochondrial outer membrane leading to cytochrome c release and cell death. However, the underlying mechanism behind Bax function remains poorly understood. Here, we studied the spatial organization of Bax in apoptotic cells using dual‐color single‐molecule localization‐based super‐resolution microscopy. We show that active Bax clustered into a broad distribution of distinct architectures, including full rings, as well as linear and arc‐shaped oligomeric assemblies that localized in discrete foci along mitochondria. Remarkably, both rings and arcs assemblies of Bax perforated the membrane, as revealed by atomic force microscopy in lipid bilayers. Our data identify the supramolecular organization of Bax during apoptosis and support a molecular mechanism in which Bax fully or partially delineates pores of different sizes to permeabilize the mitochondrial outer membrane. 相似文献
146.
147.
Interferon effects on microfilament organization cellular fibronectin distribution, and cell motility in human fibroblasts 总被引:23,自引:3,他引:20
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We have shown previously (Pfeffer et al., 1979, Exp. Cell Res. 121:111-120) that treatment of human fibroblasts, planted at a density of 2x10(3) cells/cm(2), with purified human fibroblasts interferon (640 U/ml) for 3 d at 37 degrees C decreases the overall rate of cell proliferation to 35-40 percent of the control value. In the present experiments we have characterized the phenotype of interferon-inhibited fibroblasts. The mean volume of trypsinized, interferon-treated cells was increased 31 percent abover that of control cells. The interferon-treated population was much more heterogeneous than the control population with respect to volume, and there was a considerable overlap in the volume distributions of the two populations. The cell surface area was, on the average, increased 65 percent after interferon treatment. More than 80 percent of the treated cells had enlarged nuclei, many of which were lobed, and the fraction of binucleated cells was increased fivefold. After interferon treatment, over 40 percent of the cells showed large actin-containing fibers in the form of multiple parallel arrays. Fewer than 5 percent of the control cells contained such large actin fibers. The number of actin fibers of all sizes was tripled in the treated fibroblasts on a per cell basis and, calculated per unit surface area of the cells, the number was increased 82 percent. In contrast, 10-nm filaments and microtubules did not appear to be increased in number per unit surface area of the cells. The increases per cell in the abundance of these structures were directly related to increased cell size. After interferon treatment, fibronection was distributed in arrays of long filaments covering most portions of the cell surface. Interferon treatment markedly decreased the rate of cell locomotion as well as membrane ruffling and saltatory movements of intracellular granules. 相似文献
148.
The HIV-1 gp120 envelope protein has the intrinsic capacity to stimulate monokine secretion 总被引:22,自引:0,他引:22
K A Clouse L M Cosentino K A Weih S W Pyle P B Robbins H D Hochstein V Natarajan W L Farrar 《Journal of immunology (Baltimore, Md. : 1950)》1991,147(9):2892-2901
Results and conclusions concerning the ability of HIV glycoprotein (gp) 120 to stimulate monokine secretion have been equivocal, based on observations using natural gp120 derived from infected human cells and a Chinese hamster ovary (CHO) cell-derived recombinant fusion protein. Current studies were designed to determine whether differences in recombinant gp120 proteins could result in failure to trigger monokine production. We found that natural gp120 could stimulate monocytes to release TNF-alpha, IL-1 beta, IL-6, and granulocyte-macrophage-CSF, and this effect could be blocked with soluble CD4. Full-length rgp120 either expressed from an adenovirus vector and purified from infected human cells, or derived from CHO cells, could function similarly. In contrast, full-length recombinant envelope protein expressed in a baculovirus system and a CHO cell-derived recombinant fusion protein tested previously, consistently failed to stimulate monokine production. The stimulatory capacity of both natural and full-length CHO cell-derived gp120 was eliminated by heating at 100 degrees C, and could be blocked with excess CHO cell-derived gp120 fusion protein. Inasmuch as the baculovirus-expressed gp120 and the CHO cell-derived recombinant fusion protein can bind to CD4, these results suggest that HIV gp120 binding to CD4 on the monocyte surface may of itself be insufficient for stimulation of monokine secretion. Therefore, primary protein structure, as well as posttranslational protein modifications, may determine this activity. 相似文献
149.
Specific inhibition of ribonucleotide reductases by peptides corresponding to the C-terminal of their second subunit 总被引:3,自引:0,他引:3
G Cosentino P Lavallée S Rakhit R Plante Y Gaudette C Lawetz P W Whitehead J S Duceppe C Lépine-Frenette N Dansereau 《Biochimie et biologie cellulaire》1991,69(1):79-83
Previous studies have shown that herpes virus ribonucleotide reductase can be inhibited by a synthetic nonapeptide whose sequence is identical to the C-terminal of the small subunit of the enzyme. This peptide is able to interfere with normal subunit association that takes place through the C-terminal of the small subunit. In this report, we illustrate that inhibition of ribonucleotide reductases by peptides corresponding to the C-terminal of subunit R2 is also observed for the enzyme isolated from Escherichia coli, hamster, and human cells. The nonapeptide corresponding to the bacterial C-terminal sequence was found to inhibit E. coli enzyme with an IC50 of 400 microM, while this peptide had no effect on mammalian ribonucleotide reductase. A corresponding synthetic peptide derived from the C-terminal of the small subunit of the human enzyme inhibited both human and hamster ribonucleotide reductases with IC50 values of 160 and 120 microM, respectively. However, this peptide had no inhibitory activity against the bacterial enzyme. Equivalent peptides derived from herpes virus ribonucleotide reductase had no effect on either the bacterial or mammalian enzymes. Thus, subunit association at the C-terminal of the small subunit appears to be a common feature of ribonucleotide reductases. In addition, the inhibitory phenomenon observed with peptides corresponding to the C-terminal appears not only to be universal, but also specific to the primary sequence of the enzyme. 相似文献
150.
Danielle-Julie Carrier Gregory Cosentino Ronald Neufeld Denis Rho Martin Weber Jean Archambault 《Plant cell reports》1990,8(11):635-638
Calli were obtained from Ginkgo biloba embryos grown on Murashige and Skoog (MS) medium. The G. biloba cells could grow on either MS or Gamborg B5 mineral salt medium supplemented with sucrose (3% and 2%, respectively) and naphthaleneacetic acid (NAA) and kinetin (K) in concentrations ranging from 0.1 to 2.0 mg·L–1. Best growth and maintenance of callus cultures were achieved using MS medium supplemented with 2 mg·L–1 NAA and 1 mg·L–1 K (N2K1MS). Light was required to maintain healthy growth of the callus tissue.In both MS and B5 based media, sucrose was hydrolyzed extracellularly before being taken up by Ginkgo cell suspension cultures. Specific growth rates of 0.13 d–1 and 0.08 d–1 were obtained in MS medium supplemented with 1 mg·L–1 NAA, 0.1 mg·L–1 K and 30 g·L–1 sucrose (N1K0.1MS) and B5 medium supplemented with the same growth regulator regime and 20 g·L–1 sucrose (N1K0.1B5) respectively. Complete phosphate and ammonium uptake was observed in 11 days when cultured in MS medium and 10 days and 4 days respectively when cultured in B5 medium. During the culture, G. biloba cells consumed only 64% and 29% of the nitrate content of N1K0.1MS and N1K0.1B5 media respectively. Maximum dry biomass concentrations were 13.4 g·L–1 and 7.9 g·L–1, and yields on carbohydrate were 0.39 and 0.45 in N1K0.1MS and N1K0.1B5 media respectively. The better performance of MS cultures came from the higher sucrose and nitrogen salts concentrations of this medium.Abbreviations B5
Gamborg mineral salt medium
- d.w.
Dry weight
- K
Kinetin
- MS
Murashige and Skoog mineral salt medium
- N or NAA
Naphthaleneacetic acid
- NiKjMS
i and j are the respective concentrations (mg·L–1) of NAA and K
- n
Number of experimental points
- r
Linear regression correlation coefficient 相似文献