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11.
12.
In Caenorhabditis
elegans pretreatment with juglone, a generator of reactive oxygen species (ROS) provides a subsequently increased ROS-resistance.
We investigated whether juglone at low or high concentrations when provided via the oral route in a liquid axenic medium affects
normal lifespan of C.
elegans. High juglone concentrations led to premature death, low concentrations were tolerated well and caused a prolongation of
lifespan. Lifespan extension under moderate oxidative stress was associated with increased expression of small heat-shock
protein HSP-16.2, enhanced glutathione levels, and nuclear translocation of DAF-16. Silencing or deletion of DAF-16 prevented
the juglone-induced adaptations. RNA-interference for SIR-2.1 had the same effects as the deletion of DAF-16 but did not affect
nuclear accumulation of DAF-16. Our studies demonstrate that DAF-16- and SIR-2.1-dependent alterations in gene expression
after a ROS challenge lead to a lifespan extension in C.
elegans as long as the stressor concentration does not exceed the saturable protective capacity. 相似文献
13.
Determinants of prenatal exposure to polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in an urban population 总被引:2,自引:0,他引:2 下载免费PDF全文
Herbstman JB Sjödin A Apelberg BJ Witter FR Patterson DG Halden RU Jones RS Park A Zhang Y Heidler J Needham LL Goldman LR 《Environmental health perspectives》2007,115(12):1794-1800
BACKGROUND: Recent studies have reported blood levels of polybrominated diphenyl ethers (PBDEs) in the U.S. population. Information about neonatal levels and about the relationship to polychlorinated biphenyls (PCBs) exposures is limited. OBJECTIVES: The objective was to characterize levels and determinants of fetal exposure to PBDEs and PCBs among newborns from Baltimore, Maryland. METHODS: We analyzed umbilical cord blood for eight PBDEs and 35 PCBs from infants delivered at the Johns Hopkins Hospital. Maternal and infant characteristics were abstracted from medical records. RESULTS: Ninety-four percent of cord serum samples had quantifiable levels of at least one PBDE congener, and > 99% had at least one detectable PCB congener. PBDE concentrations in cord blood were similar to those reported in other studies from North America. Strong correlations were observed within but not across PCB and PBDE classes. Multivariate models showed that many factors independently predicted exposure to BDE-47, BDE-100, and BDE-153 and CB-118, CB-138/158, CB-153, and CB-180. Generally, infants of Asian mothers had lower PBDE and PCB levels, and infants of smokers had higher levels. Increased maternal body mass index was associated with lower levels of PCBs but not PBDEs. Levels of PCBs but not PBDEs were lower in births from married and multiparous mothers. Increased maternal age was associated with higher PCB levels but lower PBDE levels. CONCLUSIONS: Although many of the factors we investigated were independent predictors of both PBDE and PCB levels, in some cases the direction of associations was different. More research is needed to better understand the sources and pathways of PBDE exposure. 相似文献
14.
The AUR1 gene in Saccharomyces cerevisiae encodes dominant resistance to the antifungal agent aureobasidin A (LY295337). 总被引:2,自引:0,他引:2 下载免费PDF全文
Aureobasidin A (LY295337) is a cyclic depsipeptide antifungal agent with activity against Candida spp. The mechanism of action of LY295337 remains unknown. LY295337 also shows activity against the yeast Saccharomyces cerevisiae. Generation of a mutant of S. cerevisiae resistant to LY295337 is reported. Resistance was found to reside in a dominant mutation of a single gene which has been named AUR1 (aureobasidin resistance). This gene was cloned and sequenced. A search for homologous sequences in GenBank and by BLAST did not elucidate the function of this gene, although sequence homology too an open reading frame from the Saccharomyces genome sequencing project and several other adjacent loci was noted. Deletion of aur1 was accomplished in a diploid S. cerevisiae strain. Subsequent sporulation and dissection of the aur1/aur1 delta diploid resulted in tetrads demonstrating 2:2 segregation of viable and nonviable spores, indicating that deletion of aur1 is lethal. As LY295337 is fungicidal and deletion of aur1 is lethal, aur1 represents a potential candidate for the target of LY295337. 相似文献
15.
16.
S. Betty Yan Victoria L. Peek Rose Ajamie Sean G. Buchanan Jeremy R. Graff Steven A. Heidler Yu-Hua Hui Karen L. Huss Bruce W. Konicek Jason R. Manro Chuan Shih Julie A. Stewart Trent R. Stewart Stephanie L. Stout Mark T. Uhlik Suzane L. Um Yong Wang Wenjuan Wu Lei Yan Wei J. Yang Boyu Zhong Richard A. Walgren 《Investigational new drugs》2013,31(4):833-844
17.
E. H. J. Weil P. H. A. Eerdmans G. A. Dijkman K. Tamussino J. Feyereisl M. E. Vierhout C. Schmidbauer C. Egarter D. Kölle J. E. M. H. Plasman H. Heidler B. E. Abbühl W. Wein 《International urogynecology journal》1998,9(3):145-150
Midodrine is a potent and selective 1-receptor agonist and its potential to increase urethral closure pressure could be useful in the treatment of female stress incontinence. The aim of this randomized double-blind placebo-controlled multicenter study was to evaluate the efficacy and safety of midodrine for the treatment of stress urinary incontinence. The primary criterion of efficacy was the maximum urethral closure pressure at rest. Voiding diaries, symptom and incontinence questionnaires and patient/investigator global assessment were also used to evaluate its efficacy. After 4 weeks of treatment no significant changes in MUCP were found. The global assessment by the patient and investigator did indicate that patients on active treatment had a more positive assessment than the placebo group. In conclusion, midodrine did not cause significant improvements in urodynamic parameters, but there were subjective improvements in some of the patients in the treated groups. Furthermore midodrine was well tolerated.Editorial Comment: The authors present a controlled trial of midodrine hydrochloride in women with genuine stress incontinence. Although the primary efficacy criterion chosen was maximum urethral pressure at rest, a number of other evaluations were performed, including voiding diaries, subjective symptom questionnaires, and patient/investigator global assessment of therapeutic response. The study finds no change in urethra closure pressure at rest when taking the medication, although both patient and investigator global assessments indicate a significant therapeutic response. The study is ambitious, well accounted for in the report, and the results critically assessed by the authors. Although the results are equivocal as to the efficacy of midodrine hydrochloride in treating stress urinary incontinence, the study clearly presents and discusses the difficulties met in evaluating the pharmacological treatment of incontinence. 相似文献
18.
Heidler KM Baker K Woods K Schnizlein-Bick C Cummings OW Sidner R Foresman B Wilkes DS 《American journal of respiratory cell and molecular biology》2000,23(4):499-505
Recognition of allogeneic major histocompatibility complex (MHC) molecules expressed on donor lung antigen-presenting cells (APCs) by host T lymphocytes is believed to stimulate lung allograft rejection. However, the specific roles of donor MHC molecules in the rejection response is unknown. We report a murine model in which instilling allogeneic lung APCs into recipient lungs induces pathology analogous to acute rejection, and the production of interferon (IFN)-gamma, immunoglobulin (Ig) G2a, and alloantibodies in recipient lungs. Using allogeneic lung APCs (C57BL/6, I-a(b), H-2(b)) deficient in MHC class I, II, or both for instillation into lungs of BALB/c mice (I-a(d), H-2(d)), the purpose of the current study was to determine the specific roles of donor MHC molecules in stimulating local alloimmune responses. The data show that MHC class I or II on donor APCs induced IFN-gamma and IgG2a synthesis locally, though less than that induced by wild-type cells. Both MHC class I and II were required to induce alloantibody production. Instillation of wild-type or class I- or class II-deficient APCs induced comparable pathologic lesions in recipient lungs, and more severe than that induced by MHC-deficient cells. These data show that donor MHC class I and II molecules have differential effects in the stimulation of local alloimmune responses. 相似文献
19.
A tripartite cytolytic toxin formed by Vibrio cholerae proteins with flagellum-facilitated secretion
Aftab Nadeem Raghavendra Nagampalli Eric Toh Athar Alam Si Lhyam Myint Thomas V. Heidler Mitesh Dongre Nikola Zlatkov Hudson Pace Fouzia Bano Anders Sjstedt Marta Bally Bernt Eric Uhlin Sun Nyunt Wai Karina Persson 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(47)
The protein MakA was discovered as a motility-associated secreted toxin from Vibrio cholerae. Here, we show that MakA is part of a gene cluster encoding four additional proteins: MakB, MakC, MakD, and MakE. MakA, MakB, and MakE were readily detected in culture supernatants of wild-type V. cholerae, whereas secretion was very much reduced from a flagellum-deficient mutant. Crystal structures of MakA, MakB, and MakE revealed a structural relationship to a superfamily of bacterial pore-forming toxins. Expression of MakA/B/E in Escherichia coli resulted in toxicity toward Caenorhabditis elegans used as a predatory model organism. None of these Mak proteins alone or in pairwise combinations were cytolytic, but an equimolar mixture of MakA, MakB, and MakE acted as a tripartite cytolytic toxin in vitro, causing lysis of erythrocytes and cytotoxicity on cultured human colon carcinoma cells. Formation of oligomeric complexes on liposomes was observed by electron microscopy. Oligomer interaction with membranes was initiated by MakA membrane binding followed by MakB and MakE joining the assembly of a pore structure. A predicted membrane insertion domain of MakA was shown by site-directed mutagenesis to be essential for toxicity toward C. elegans. Bioinformatic analyses revealed that the makCDBAE gene cluster is present as a genomic island in the vast majority of sequenced genomes of V. cholerae and the fish pathogen Vibrio anguillarum. We suggest that the hitherto-unrecognized cytolytic MakA/B/E toxin can contribute to Vibrionaceae fitness and virulence potential in different host environments and organisms.Vibrio cholerae is known as the cause of cholera, a disease that can lead to fatal dehydration (1). The disease is caused by a few serogroups, and the main factor behind the symptoms is the cholera toxin (CT) encoded by genes located on a prophage mobile genetic element (CTX-φ) that induce severe disruption of intestinal cell function, leading to watery, secretory diarrhea (2). Most serogroups do not cause cholera, as they do not possess the genes for CT, but they cause other diseases [e.g., skin, wound, and gastrointestinal infections as well as bacteremia (3)]. The natural reservoirs of V. cholerae are aquatic sources such as rivers, brackish waters, and estuaries and are often associated with copepods, aquatic plants, and shellfish (4). The factors and mechanisms allowing V. cholerae and other Vibrionaceae to survive and thrive in harsh natural environments are of major interest to researchers (5).V. cholerae is motile by virtue of a single polar flagellum. The flagellum export machinery and the virulence-associated type-III secretion system (fT3SS and vT3SS, respectively) are suggested to share a common ancestor (6), explaining their similar structure and molecular organization. The vT3SS allows the delivery of effector proteins through a hollow channel directly to the eukaryotic host cell (7), and flagellar proteins are delivered via the fT3SS channel during flagellum assembly. In the bacterial cytoplasm, effectors secreted by the vT3SS are stabilized by chaperones to prevent aggregation. These chaperones are often encoded by genes adjacent to those encoding the effectors (8). Flagellar proteins are similarly protected by chaperones before they are transported to the growing distal end of the flagellum (9).We use Caenorhabditis elegans as a predatory organism model for identifying and assessing V. cholerae factors, other than CT, that may contribute to bacterial survival and persistence (10). With this model, we discovered a cytotoxin, MakA (motility-associated killing factor A), which we demonstrated to be an essential factor for the cytotoxic activity of V. cholerae in both C. elegans and Danio rerio (zebrafish) (11). We also demonstrated that secretion of MakA occurs via the flagellum in a manner that is undocumented in V. cholerae. Our crystal structure of MakA revealed similarities to ClyA (11), the pore-forming toxin first identified in nonpathogenic Escherichia coli (12, 13) and, subsequently, also in Salmonella enterica (14). ClyA from E. coli is expressed from a monocistronic operon and oligomerizes into a dodecameric pore upon release via membrane vesicles (13, 15, 16). MakA is also structurally related to two proteins from Bacillus cereus, the hemolysin BL binding component B (HBL-B) and the NheA component of the Nhe nonhemolytic enterotoxin. Both of these are considered components of tripartite toxins (17). Recently, a tripartite toxin, AhlABC, was identified and structurally characterized as a pore-forming toxin in Aeromonas hydrophila, and the structure of soluble AhlB shares the general structure described for MakA (18). A similar toxin complex of three proteins, SmhABC from Serratia marcescens, was also reported (19). However, if and how the Ahl and Smh proteins are released during normal growth, or if there is a dedicated secretion system, remain unclear.Here, we identify the proteins from the five V. cholerae genes, vca0880 through vca0884, that are coexpressed from the operon makDCBAE and analyze the crystal structures of MakA, MakB, and MakE. Our in vitro studies revealed that an equimolar combination of the MakA/B/E proteins acted as a tripartite cytotoxin causing lysis of red blood cells and cytotoxicity to epithelial cells. Examination of a large number of bacterial genomes revealed that the mak operon is present in many V. cholerae and other Vibrionaceae strains. These include Vibrio (Listonella) anguillarum, an inhabitant of estuarine and marine coastal ecosystems worldwide and the etiological agent of vibriosis in warm- and cold-water fish (20). The identification and structural characterization of the Mak proteins in V. cholerae presented here reveals a hitherto-unrecognized potential of many pathogenic Vibrionaceae strains to produce the tripartite Mak cytolytic toxin. 相似文献
20.