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51.
Duarte CD Tributino JL Lacerda DI Martins MV Alexandre-Moreira MS Dutra F Bechara EJ De-Paula FS Goulart MO Ferreira J Calixto JB Nunes MP Bertho AL Miranda AL Barreiro EJ Fraga CA 《Bioorganic & medicinal chemistry》2007,15(6):2421-2433
We describe herein the discovery of LASSBio-881 (3c) as a novel in vivo antinociceptive, anti-inflammatory, and in vitro antiproliferative and antioxidant compound, with a cannabinoid ligand profile. We observed that LASSBio-881 (3c) was able to bind to CB1 receptors (71% at 100microM) and also to inhibit T-cell proliferation (66% at 10microM) probably by binding to CB2 receptors, in a non-proapoptotic manner, different from anandamide (1). It was also demonstrated that LASSBio-881 (3c) had an important antioxidant profile toward free radicals (DPPH and hydroxyl), probably due to its particular redox behavior, which reflects the presence of both nitro and 3,5-di-tert-butyl-4-hydroxyphenyl sub-units, as demonstrated by cyclic voltammetry studies. In addition, we showed that these structural sub-units are essential for the observed pharmacological activity. 相似文献
52.
Chlorophyllase is a rate-limiting enzyme in chlorophyll catabolism and is posttranslationally regulated 总被引:2,自引:0,他引:2
Harpaz-Saad S Azoulay T Arazi T Ben-Yaakov E Mett A Shiboleth YM Hörtensteiner S Gidoni D Gal-On A Goldschmidt EE Eyal Y 《The Plant cell》2007,19(3):1007-1022
Chlorophyll is a central player in harvesting light energy for photosynthesis, yet the rate-limiting steps of chlorophyll catabolism and the regulation of the catabolic enzymes remain unresolved. To study the role and regulation of chlorophyllase (Chlase), the first enzyme of the chlorophyll catabolic pathway, we expressed precursor and mature versions of citrus (Citrus sinensis) Chlase in two heterologous plant systems: (1) squash (Cucurbita pepo) plants using a viral vector expression system; and (2) transiently transformed tobacco (Nicotiana tabacum) protoplasts. Expression of full-length citrus Chlase resulted in limited chlorophyll breakdown in protoplasts and no visible leaf phenotype in whole plants, whereas expression of a Chlase version lacking the N-terminal 21 amino acids (ChlaseDeltaN), which corresponds to the mature protein, led to extensive chlorophyll breakdown in both tobacco protoplasts and squash leaves. ChlaseDeltaN-expressing squash leaves displayed a dramatic chlorotic phenotype in plants grown under low-intensity light, whereas under natural light a lesion-mimic phenotype occurred, which was demonstrated to follow the accumulation of chlorophyllide, a photodynamic chlorophyll breakdown product. Full-length and mature citrus Chlase versions were localized to the chloroplast membrane fraction in expressing tobacco protoplasts, where processing of the N-terminal 21 amino acids appears to occur. Results obtained in both plant systems suggest that Chlase functions as a rate-limiting enzyme in chlorophyll catabolism controlled via posttranslational regulation. 相似文献
53.
Cancer is a result of complex changes that occur in normal cells as they transform to become malignant and further when they become metastatic. These changes are not a consequence of a single protein but rather involve multiple proteins that function in pathways and networks. Thus, profiling cancer-associated changes requires simultaneous measurement of many proteins in a single sample. Identifying these changes may lead to the discovery of cancer-associated biomarkers that may assist in diagnosis, prognosis, patient monitoring and possibly for therapeutic purposes. Antibody arrays are a relatively new technology that enables one to perform multiplex high-throughput protein expression profiling. This review describes current technologies in antibody array and assay design, and presents a survey of the current literature on the use of these arrays in cancer research. 相似文献
54.
Katie L Mickle Sunita Ramanathan Adam Rosebrock Anna Oliva Amna Chaudari Chulee Yompakdee Donna Scott Janet Leatherwood Joel A Huberman 《BMC molecular biology》2007,8(1):1-28
Background
In budding yeast, the replication checkpoint slows progress through S phase by inhibiting replication origin firing. In mammals, the replication checkpoint inhibits both origin firing and replication fork movement. To find out which strategy is employed in the fission yeast, Schizosaccharomyces pombe, we used microarrays to investigate the use of origins by wild-type and checkpoint-mutant strains in the presence of hydroxyurea (HU), which limits the pool of deoxyribonucleoside triphosphates (dNTPs) and activates the replication checkpoint. The checkpoint-mutant cells carried deletions either of rad3 (which encodes the fission yeast homologue of ATR) or cds1 (which encodes the fission yeast homologue of Chk2).Results
Our microarray results proved to be largely consistent with those independently obtained and recently published by three other laboratories. However, we were able to reconcile differences between the previous studies regarding the extent to which fission yeast replication origins are affected by the replication checkpoint. We found (consistent with the three previous studies after appropriate interpretation) that, in surprising contrast to budding yeast, most fission yeast origins, including both early- and late-firing origins, are not significantly affected by checkpoint mutations during replication in the presence of HU. A few origins (~3%) behaved like those in budding yeast: they replicated earlier in the checkpoint mutants than in wild type. These were located primarily in the heterochromatic subtelomeric regions of chromosomes 1 and 2. Indeed, the subtelomeric regions defined by the strongest checkpoint restraint correspond precisely to previously mapped subtelomeric heterochromatin. This observation implies that subtelomeric heterochromatin in fission yeast differs from heterochromatin at centromeres, in the mating type region, and in ribosomal DNA, since these regions replicated at least as efficiently in wild-type cells as in checkpoint-mutant cells.Conclusion
The fact that ~97% of fission yeast replication origins – both early and late – are not significantly affected by replication checkpoint mutations in HU-treated cells suggests that (i) most late-firing origins are restrained from firing in HU-treated cells by at least one checkpoint-independent mechanism, and (ii) checkpoint-dependent slowing of S phase in fission yeast when DNA is damaged may be accomplished primarily by the slowing of replication forks. 相似文献55.
Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging
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Assaf Ben‐Meir Eliezer Burstein Aluet Borrego‐Alvarez Jasmine Chong Ellen Wong Tetyana Yavorska Taline Naranian Maggie Chi Ying Wang Yaakov Bentov Jennifer Alexis James Meriano Hoon‐Ki Sung David L. Gasser Kelle H. Moley Siegfried Hekimi Robert F. Casper Andrea Jurisicova 《Aging cell》2015,14(5):887-895
Female reproductive capacity declines dramatically in the fourth decade of life as a result of an age‐related decrease in oocyte quality and quantity. The primary causes of reproductive aging and the molecular factors responsible for decreased oocyte quality remain elusive. Here, we show that aging of the female germ line is accompanied by mitochondrial dysfunction associated with decreased oxidative phosphorylation and reduced Adenosine tri‐phosphate (ATP) level. Diminished expression of the enzymes responsible for CoQ production, Pdss2 and Coq6, was observed in oocytes of older females in both mouse and human. The age‐related decline in oocyte quality and quantity could be reversed by the administration of CoQ10. Oocyte‐specific disruption of Pdss2 recapitulated many of the mitochondrial and reproductive phenotypes observed in the old females including reduced ATP production and increased meiotic spindle abnormalities, resulting in infertility. Ovarian reserve in the oocyte‐specific Pdss2‐deficient animals was diminished, leading to premature ovarian failure which could be prevented by maternal dietary administration of CoQ10. We conclude that impaired mitochondrial performance created by suboptimal CoQ10 availability can drive age‐associated oocyte deficits causing infertility. 相似文献
56.
Spencer B Marr RA Gindi R Potkar R Michael S Adame A Rockenstein E Verma IM Masliah E 《PloS one》2011,6(1):e16575
Alzheimer's disease (AD), an incurable, progressive neurodegenerative disorder, is the most common form of dementia. Therapeutic options have been elusive due to the inability to deliver proteins across the blood-brain barrier (BBB). In order to improve the therapeutic potential for AD, we utilized a promising new approach for delivery of proteins across the BBB. We generated a lentivirus vector expressing the amyloid β-degrading enzyme, neprilysin, fused to the ApoB transport domain and delivered this by intra-peritoneal injection to amyloid protein precursor (APP) transgenic model of AD. Treated mice had reduced levels of Aβ, reduced plaques and increased synaptic density in the CNS. Furthermore, mice treated with the neprilysin targeting the CNS had a reversal of memory deficits. Thus, the addition of the ApoB transport domain to the secreted neprilysin generated a non-invasive therapeutic approach that may be a potential treatment in patients with AD. 相似文献
57.
Masliah E Rockenstein E Adame A Alford M Crews L Hashimoto M Seubert P Lee M Goldstein J Chilcote T Games D Schenk D 《Neuron》2005,46(6):857-868
Abnormal folding of alpha-synuclein (alpha-syn) is thought to lead to neurodegeneration and the characteristic symptoms of Lewy body disease (LBD). Since previous studies suggest that immunization might be a potential therapy for Alzheimer's disease, we hypothesized that immunization with human (h)alpha-syn might have therapeutic effects in LBD. For this purpose, halpha-syn transgenic (tg) mice were vaccinated with halpha-syn. In mice that produced high relative affinity antibodies, there was decreased accumulation of aggregated halpha-syn in neuronal cell bodies and synapses that was associated with reduced neurodegeneration. Furthermore, antibodies produced by immunized mice recognized abnormal halpha-syn associated with the neuronal membrane and promoted the degradation of halpha-syn aggregates, probably via lysosomal pathways. Similar effects were observed with an exogenously applied FITC-tagged halpha-syn antibody. These results suggest that vaccination is effective in reducing neuronal accumulation of halpha-syn aggregates and that further development of this approach might have a potential role in the treatment of LBD. 相似文献
58.
Hashimoto M Bar-On P Ho G Takenouchi T Rockenstein E Crews L Masliah E 《The Journal of biological chemistry》2004,279(22):23622-23629
Recent studies have shown that the neurodegenerative process in disorders with Lewy body formation, such as Parkinson's disease and dementia with Lewy bodies, is associated with alpha-synuclein accumulation and that beta-synuclein might protect the central nervous system from the neurotoxic effects of alpha-synuclein. However, the mechanisms are unclear. The main objective of the present study was to investigate the potential involvement of the serine threonine kinase Akt (also known as protein kinase B) signaling pathway in the mechanisms of beta-synuclein neuroprotection. For this purpose, Akt activity and cell survival were analyzed in synuclein-transfected B103 neuroblastoma cells and primary cortical neurons. Beta-synuclein transfection resulted in increased Akt activity and conferred protection from the neurotoxic effects of rotenone. Down-regulation of Akt expression resulted in an increased susceptibility to rotenone toxicity, whereas transfection with a lentiviral vector encoding for beta-synuclein was protective. The effects of beta-synuclein on the Akt pathway appear to be by direct interaction between these molecules and were independent of upstream signaling molecules. Taken together, these results indicate that the mechanisms of beta-synuclein neuroprotection might involve direct interactions between beta-synuclein and Akt and suggest that this signaling pathway could be a potential therapeutic target for neurological conditions associated with parkinsonism and alpha-synuclein aggregation. 相似文献
59.
Elka R. Georgieva Trudy F. Ramlall Peter P. Borbat Jack H. Freed David Eliezer 《The Journal of biological chemistry》2010,285(36):28261-28274
α-Synuclein (αS) is linked to Parkinson disease through its deposition in an amyloid fibril form within Lewy Body deposits, and by the existence of three αS point mutations that lead to early onset autosomal dominant Parkinsonism. The normal function of αS is thought to be linked to the ability of the protein to bind to the surface of synaptic vesicles. Upon binding to vesicles, αS undergoes a structural reorganization from a dynamic and disordered ensemble to a conformation consisting of a long extended helix. In the presence of small spheroidal detergent micelles, however, this extended helix conformation can convert into a broken helix state, in which a region near the middle of the helix unwinds to form a linker between the two resulting separated helices. Membrane-bound conformations of αS likely mediate the function of the protein, but may also play a role in the aggregation and toxicity of the protein. Here we have undertaken a study of the effects of the three known PD-linked mutations on the detergent- and membrane-bound conformations of αS, as well as factors that govern the transition of the protein between the extended helix and broken helix states. Using pulsed dipolar ESR measurements of distances up to 8.7 nm, we show that all three PD-linked αS mutants retain the ability to transition from the broken helix to the extended helix conformation. In addition, we find that the ratio of protein to detergent, rather than just the absolute detergent concentration, determines whether the protein adopts the broken or extended helix conformation. 相似文献
60.