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排序方式: 共有395条查询结果,搜索用时 156 毫秒
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Mohammad-Reza Ghovanloo Koushik Choudhury Tagore S. Bandaru Mohamed A. Fouda Kaveh Rayani Radda Rusinova Tejas Phaterpekar Karen Nelkenbrecher Abeline R. Watkins Damon Poburko Jenifer Thewalt Olaf S. Andersen Lucie Delemotte Samuel J. Goodchild Peter C. Ruben 《The Journal of general physiology》2021,153(5)
Cannabidiol (CBD) is the primary nonpsychotropic phytocannabinoid found in Cannabis sativa, which has been proposed to be therapeutic against many conditions, including muscle spasms. Among its putative targets are voltage-gated sodium channels (Navs), which have been implicated in many conditions. We investigated the effects of CBD on Nav1.4, the skeletal muscle Nav subtype. We explored direct effects, involving physical block of the Nav pore, as well as indirect effects, involving modulation of membrane elasticity that contributes to Nav inhibition. MD simulations revealed CBD’s localization inside the membrane and effects on bilayer properties. Nuclear magnetic resonance (NMR) confirmed these results, showing CBD localizing below membrane headgroups. To determine the functional implications of these findings, we used a gramicidin-based fluorescence assay to show that CBD alters membrane elasticity or thickness, which could alter Nav function through bilayer-mediated regulation. Site-directed mutagenesis in the vicinity of the Nav1.4 pore revealed that removing the local anesthetic binding site with F1586A reduces the block of INa by CBD. Altering the fenestrations in the bilayer-spanning domain with Nav1.4-WWWW blocked CBD access from the membrane into the Nav1.4 pore (as judged by MD). The stabilization of inactivation, however, persisted in WWWW, which we ascribe to CBD-induced changes in membrane elasticity. To investigate the potential therapeutic value of CBD against Nav1.4 channelopathies, we used a pathogenic Nav1.4 variant, P1158S, which causes myotonia and periodic paralysis. CBD reduces excitability in both wild-type and the P1158S variant. Our in vitro and in silico results suggest that CBD may have therapeutic value against Nav1.4 hyperexcitability. 相似文献
3.
Martina Bernardi Elena Albiero Alberta Alghisi Katia Chieregato Chiara Lievore Domenico Madeo Francesco Rodeghiero Giuseppe Astori 《Cytotherapy》2013,15(8):920-929
Background aimsA medium supplemented with fetal bovine serum (FBS) is of common use for the expansion of human mesenchymal stromal cells (MSCs). However, its use is discouraged by regulatory authorities because of the risk of zoonoses and immune reactions. Human platelet lysate (PL) obtained by freezing/thawing disruption of platelets has been proposed as a possible substitute of FBS. The process is time-consuming and not well standardized. A new method for obtaining PL that is based on the use of ultrasound is proposed.MethodsPlatelet sonication was performed by submerging platelet-containing plastic bags in an ultrasonic bath. To evaluate platelet lysis we measured platelet-derived growth factor-AB release. PL efficiency was tested by expanding bone marrow (BM)-MSCs, measuring population doubling time, differentiation capacity and immunogenic properties. Safety was evaluated by karyotyping expanded cells.ResultsAfter 30 minutes of sonication, 74% of platelet derived growth factor-AB was released. PL enhanced BM-MSC proliferation rate compared with FBS. The mean cumulative population doubling (cPD) of cells growth in PL at 10%, 7.5% and 5% was better compared with cPD obtained with 10% FBS. PD time (hours) of MSCs with PL obtained by sonication was shorter than for cPD with PL obtained by freezing/thawing (18.9 versus 17.4, P < 0.01). BM mononucleated cells expressed MSC markers and were able to differentiate into adipogenic, osteogenic and chondrogenic lineages. When BM-MSCs and T cells were co-cultured in close contact, immunosuppressive activity of BM-MSCs was maintained. Cell karyotype showed no genetic alterations.ConclusionsThe proposed method for the production of PL by sonication could be a safe, efficient and fast substitute of FBS, without the potential risks of FBS. 相似文献
4.
Didac Carmona-Gutierrez Ali Alavian-Ghavanini Lukas Habernig Maria Anna Bauer Astrid Hammer Christine Rossmann Andreas S. Zimmermann Christoph Ruckenstuhl Sabrina Büttner Tobias Eisenberg Wolfgang Sattler Ernst Malle Frank Madeo 《Cell cycle (Georgetown, Tex.)》2013,12(11):1704-1712
Following microbial pathogen invasion, the human immune system of activated phagocytes generates and releases the potent oxidant hypochlorous acid (HOCl), which contributes to the killing of menacing microorganisms. Though tightly controlled, HOCl generation by the myeloperoxidase-hydrogen peroxide-chloride system of neutrophils/monocytes may occur in excess and lead to tissue damage. It is thus of marked importance to delineate the molecular pathways underlying HOCl cytotoxicity in both microbial and human cells. Here, we show that HOCl induces the generation of reactive oxygen species (ROS), apoptotic cell death and the formation of specific HOCl-modified epitopes in the budding yeast Saccharomyces cerevisiae. Interestingly, HOCl cytotoxicity can be prevented by treatment with ROS scavengers, suggesting oxidative stress to mediate the lethal effect. The executing pathway involves the pro-apoptotic protease Kex1p, since its absence diminishes HOCl-induced production of ROS, apoptosis and protein modification. By characterizing HOCl-induced cell death in yeast and identifying a corresponding central executor, these results pave the way for the use of Saccharomyces cerevisiae in HOCl research, not least given that it combines both being a microorganism as well as a model for programmed cell death in higher eukaryotes. 相似文献
5.
Zaida Araujo Francesca Giampietro María de los Angeles Bochichio Andrea Palacios Jenifer Dinis Jaime Isern Jacobus Henry de Waard Elsa Rada Rafael Borges Carlos Fernández de Larrea Angel Villasmil Magnolia Vanegas Jose Antonio Enciso-Moreno Manuel Alfonso Patarroyo 《Memórias do Instituto Oswaldo Cruz》2013,108(2):131-139
The goal of this study was to demonstrate the usefulness of an enzyme-linked immunosorbent assay (ELISA) for the serodiagnosis of pulmonary tuberculosis (PTB) and extrapulmonary TB (EPTB). This assay used 20 amino acid-long, non-overlapped synthetic peptides that spanned the complete Mycobacterium tuberculosis ESAT-6 and Ag85A sequences. The validation cohort consisted of 1,102 individuals who were grouped into the following five diagnostic groups: 455 patients with PTB, 60 patients with EPTB, 40 individuals with non-EPTB, 33 individuals with leprosy and 514 healthy controls. For the PTB group, two ESAT-6 peptides (12033 and 12034) had the highest sensitivity levels of 96.9% and 96.2%, respectively, and an Ag85A-peptide (29878) was the most specific (97.4%) in the PTB groups. For the EPTB group, two Ag85A peptides (11005 and 11006) were observed to have a sensitivity of 98.3% and an Ag85A-peptide (29878) was also the most specific (96.4%). When combinations of peptides were used, such as 12033 and 12034 or 11005 and 11006, 99.5% and 100% sensitivities in the PTB and EPTB groups were observed, respectively. In conclusion, for a cohort that consists entirely of individuals from Venezuela, a multi-antigen immunoassay using highly sensitive ESAT-6 and Ag85A peptides alone and in combination could be used to more rapidly diagnose PTB and EPTB infection. 相似文献
6.
Jenifer L. Smith Kassandra I. Rossiter Christopher M. Semko Ying-Zi Xu David A. Quincy Jacek Jagodzinski Michael S. Dappen Andrei W. Konradi Christopher Vandevert Caroline Garrido Wenxian Mao F. Bong San Pablo Brian Wipke Lilibeth Dofiles Angie Wadsworth Eric Peterson Carlos Lorenzana Stellanie Simmonds Ted A. Yednock 《Bioorganic & medicinal chemistry letters》2013,23(14):4117-4119
Mitsunobu reactions were employed to link t-butyl esters of α4 integrin inhibitors at each of the termini of a three-arm, 40 kDa, branched PEG. Cleavage of the t-butyl esters using HCO2H provided easily isolated PEG derivatives, which are potent α4 integrin inhibitors, and which achieve sustained levels and bioactivity in vivo, following subcutaneous administration to rats. 相似文献
7.
Daniel Medina Myra C. Hughey Jenifer B. Walke Matthew H. Becker Katherine Pontarelli Shan Sun Brian Badgley Lisa K. Belden 《Environmental microbiology》2019,21(8):2905-2920
Amphibian population declines caused by the fungus Batrachochytrium dendrobatidis (Bd) have prompted studies on the bacterial community that resides on amphibian skin. However, studies addressing the fungal portion of these symbiont communities have lagged behind. Using ITS1 amplicon sequencing, we examined the fungal portion of the skin microbiome of temperate and tropical amphibian species currently coexisting with Bd in nature. We assessed cooccurrence patterns between bacterial and fungal OTUs using a subset of samples for which bacterial 16S rRNA gene amplicon data were also available. We determined that fungal communities were dominated by members of the phyla Ascomycota and Basidiomycota, and also by Chytridiomycota in the most aquatic amphibian species. Alpha diversity of the fungal communities differed across host species, and fungal community structure differed across species and regions. However, we did not find a correlation between fungal diversity/community structure and Bd infection, though we did identify significant correlations between Bd and specific OTUs. Moreover, positive bacterial–fungal cooccurrences suggest that positive interactions between these organisms occur in the skin microbiome. Understanding the ecology of amphibian skin fungi, and their interactions with bacteria will complement our knowledge of the factors influencing community assembly and the overall function of these symbiont communities. 相似文献
8.
Lingpeng?Cheng Senxiong?Chen Jenifer?M.?Brannan Joanita?Jakana Qinfen?Zhang Z.?H.?Zhou Jingqiang?ZhangEmail author 《中国科学C辑(英文版)》2004,47(3):224-228
The three-dimensional structure of capsid ofAedes albopictus C6/36 densovirus was determined to 14-Å resolution by electron cryomicroscopy and computer reconstruction. The triangulation number of the capsid is 1. There are 12 holes in each triangular face and a spike on each 5-fold vertex. The validity of the capsid and nucleic acid densities in the reconstructions was discussed. 相似文献
9.
Yeast lacking the SRO7/SOP1-encoded tumor suppressor homologue show increased susceptibility to apoptosis-like cell death on exposure to NaCl stress 总被引:7,自引:0,他引:7 下载免费PDF全文
Yeast cells deleted for the SRO7/SOP1 encoded tumor suppressor homologue show increased sensitivity to NaCl stress. On exposure to growth-inhibiting NaCl concentrations, sro7Delta mutants display a rapid loss in viability that is associated with markers of apoptosis: accumulation of reactive oxygen species, DNA breakage, and nuclear fragmentation. Additional deletion of the yeast metacaspase gene YCA1 prevents the primary fast drop in viability and diminishes nuclear fragmentation and DNA breakage. We also observed that NaCl induced loss in viability of wild-type cells is Yca1p dependent. However, a yeast strain deleted for both SRO7 and its homologue SRO77 exhibits NaCl-induced cell death that is independent on YCA1. Likewise, sro77Delta single mutants do not survive better after additional deletion of the YCA1 gene, and both sro77Delta and sro77Deltayca1Delta mutants display apoptotic characteristics when exposed to growth-inhibiting salinity, suggesting that yeast possesses Yca1p-independent pathway(s) for apoptosis-like cell death. The activity of Yca1p increases with increasing NaCl stress and sro7Delta mutants achieve levels that are higher than in wild-type cells. However, mutants lacking SRO77 do not enhance caspase activity when subject to NaCl stress, suggesting that Sro7p and Sro77p exert opposing effects on the cellular activity of Yca1p. 相似文献
10.
Vincenzo?Rochira Matteo?Fabbi Elena?Valassi Bruno?Madeo Cesare?CaraniEmail author 《Andrologie》2003,13(1):57-61
The role of estrogen on male reproductive function has become clearer in the last decade. During these years the study of
the effect of testosterone, estrogen or an aromatase inhibitor in hypogonadal men provided a first evidence of the effects
of estrogens in the regulation of gonadotropin secretion. At the same time, the development of a line of transgenic male mice
lacking estrogen receptor α, estrogen receptor β or aromatase gene provided further evidence about the role of estrogens not
only in the regulation of gonadotropin secretion, but also on the effects of estrogens on testicular function and development.
A confirmation of these actions of estrogens came from the observation of naturally occurring mutations of the estrogen receptor
and of the aromatase gene in human males. Based on these data it has been demonstrated that estrogens are major regulators
of gonadotropin secretion acting both at pituitary and hypotalamic level. The presence in the human reproductive structures
of estrogen receptor α, estrogen receptor β and the aromatase enzyme indicates the existence of receptor α, estrogen receptor
β or aromatase estrogen actions at this level. Anyway, the precise role of estrogens in testicular development and function
and on the regulation of human spermatogenesis has not yet been precisely clarified. 相似文献