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521.
Victor N. Uebele Cindy E. Nuss Steven V. Fox Susan L. Garson Razvan Cristescu Scott M. Doran Richard L. Kraus Vincent P. Santarelli Yuxing Li James C. Barrow Zhi-Qiang Yang Kelly-Ann S. Schlegel Kenneth E. Rittle Thomas S. Reger Rodney A. Bednar Wei Lemaire Faith A. Mullen Jeanine E. Ballard Cuyue Tang Ge Dai Owen B. McManus Kenneth S. Koblan John J. Renger 《Cell biochemistry and biophysics》2009,55(2):81-93
Low-voltage-activated (T-type) calcium channels play a role in diverse physiological responses including neuronal burst firing, hormone secretion, and cell growth. To better understand the biological role and therapeutic potential of the target, a number of structurally diverse antagonists have been identified. Multiple drug interaction sites have been identified for L-type calcium channels, suggesting a similar possibility exists for the structurally related T-type channels. Here, we radiolabel a novel amide T-type calcium channel antagonist (TTA-A1) and show that several known antagonists, including mibefradil, flunarizine, and pimozide, displace binding in a concentration-dependent manner. Further, we identify a novel quinazolinone T-type antagonist (TTA-Q4) that enhanced amide radioligand binding, increased affinity in a saturable manner and slowed dissociation. Functional evaluation showed these compounds to be state-dependent antagonists which show a positive allosteric interaction. Consistent with slowing dissociation, the duration of efficacy was prolonged when compounds were co-administered to WAG/Rij rats, a genetic model of absence epilepsy. The development of a T-type calcium channel radioligand has been used to demonstrate structurally distinct TTAs interact at allosteric sites and to confirm the potential for synergistic inhibition of T-type calcium channels with structurally diverse antagonists. 相似文献
522.
Naira Baregamian Amie R. Ballard Dai H. Chung 《Biochemical and biophysical research communications》2009,379(2):423-1351
Necrotizing enterocolitis (NEC) remains a lethal condition for many premature infants. Peroxisome proliferator-activated receptor-γ (PPAR-γ), a member of the nuclear hormone receptor family, has been shown to play a protective role in cellular inflammatory responses; however, its role in NEC is not clearly defined. We sought to examine the expression of PPAR-γ in the intestine using an ischemia-reperfusion (I/R) model of NEC, and to assess whether PPAR-γ agonist treatment would ameliorate I/R-induced gut injury. Swiss-Webster mice were randomized to receive sham (control) or I/R injury to the gut induced by transient occlusion of superior mesenteric artery for 45 min with variable periods of reperfusion. I/R injury resulted in early induction of PPAR-γ expression and activation of NF-κB in small intestine. Pretreatment with PPAR-γ agonist, 15d-PGJ2, attenuated intestinal NF-κB response and I/R-induced gut injury. Activation of PPAR-γ demonstrated a protective effect on small bowel during I/R-induced gut injury. 相似文献
523.
Henner Knust Guido Achermann Theresa Ballard Bernd Buettelmann Rodolfo Gasser Holger Fischer Maria-Clemencia Hernandez Frédéric Knoflach Andreas Koblet Heinz Stadler Andrew W. Thomas Gerhard Trube Pius Waldmeier 《Bioorganic & medicinal chemistry letters》2009,19(20):5940-5944
Lead optimisation of the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine class led to the identification of two clinical leads [RO4882224 (11) and RO4938581 (44)] functioning as novel potent and selective GABAA α5 inverse agonists. The unique pharmacological profiles and optimal pharmacokinetic profiles resulted in in vivo activity in selected cognition models. 相似文献
524.
Dena Lyras Vicki Adams Susan A. Ballard Wee L. Teng Pauline M. Howarth Paul K. Crellin Trudi L. Bannam J. Glenn Songer Julian I. Rood 《Journal of bacteriology》2009,191(20):6345-6351
Clostridium perfringens is a normal gastrointestinal organism that is a reservoir for antibiotic resistance genes and can potentially act as a source from which mobile elements and their associated resistance determinants can be transferred to other bacterial pathogens. Lincomycin resistance in C. perfringens is common and is usually encoded by erm genes that confer macrolide-lincosamide-streptogramin B resistance. In this study we identified strains that are lincomycin resistant but erythromycin sensitive and showed that the lincomycin resistance determinant was plasmid borne and could be transferred to other C. perfringens isolates by conjugation. The plasmid, pJIR2774, is the first conjugative C. perfringens R-plasmid to be identified that does not confer tetracycline resistance. Further analysis showed that resistance was encoded by the lnuP gene, which encoded a putative lincosamide nucleotidyltransferase and was located on tISCpe8, a functional transposable genetic element that was a member of the IS1595 family of transposon-like insertion sequences. This element had significant similarity to the mobilizable lincomycin resistance element tISSag10 from Streptococcus agalactiae. Like tISSag10, tISCpe8 carries a functional origin of transfer within the resistance gene, allowing the element to be mobilized by the conjugative transposon Tn916. The similarity of these elements and the finding that they both contain an oriT-like region support the hypothesis that conjugation may result in the movement of DNA modules that are not obviously mobile since they are not linked to conjugation or mobilization functions. This process likely plays a significant role in bacterial adaptation and evolution.There has been increasing concern about the emergence of multiply antibiotic-resistant strains of many common bacterial pathogens. The development of multiple resistance phenotypes has already led to compromises in the ability to successfully treat infected patients and to increased treatment costs (15). The emergence of resistant bacteria is often the result of excessive or inappropriate use of antibiotics and the ability of antibiotic resistance genes to be transferred from resistant to susceptible bacteria, either within a bacterial species, between different species within the same genus, or between different genera (14). Different types of mobile genetic elements, including conjugative plasmids, conjugative transposons, mobilizable plasmids, mobilizable transposons, nonconjugative plasmids, and integrons, may contain the resistance genes (14). All of these elements have the ability to mediate the transfer of resistance genes within and between bacterial cells, either independently or cooperatively, which has significant implications for the transfer and evolution of antibiotic resistance, particularly in pathogenic bacterial species.Clostridium perfringens is a normal gastrointestinal organism that causes food poisoning, necrotic enteritis, and gas gangrene (29). It is a proven reservoir for antibiotic resistance determinants. For example, the catP chloramphenicol resistance determinant, which is located on the Tn4451/Tn4453 family of integrative mobilizable elements in C. perfringens and Clostridium difficile, has been detected in clinical isolates of Neisseria meningitidis (20, 23, 41). Similarly, genetically related variants of the macrolide-lincosamide-streptogramin B (MLS) resistance determinant Erm(B) from C. perfringens have been found in Enterococcus faecalis, Streptococcus agalactiae, and C. difficile (19). It is likely that the C. perfringens determinant is the progenitor of the C. difficile determinant (18, 19, 44). Significantly, both determinants can be transferred into recipient cells by conjugation, although the processes are different (12, 19, 43). The pathogenic clostridia also carry other uncharacterized MLS resistance determinants and can potentially act as a source from which these resistance determinants may be transferred to other bacterial pathogens (10, 18).Lincomycin belongs to the lincosamide group of antibiotics, which also includes clindamycin. The spectrum of activity of lincosamides predominantly encompasses gram-positive bacteria, and these antimicrobial agents are often used for treatment of infections caused by anaerobic bacteria (45). These antibiotics inhibit protein synthesis by blocking the peptidyltransferase site of the 23S rRNA component of the 50S subunit of the bacterial ribosome (17). Although cross-resistance to MLS antibiotics most commonly involves N6 dimethylation of the A2058 residue of 23S rRNA and is catalyzed by an erm-encoded rRNA methyltransferase (24, 34, 47), specific resistance to the lincosamides is the result of modification and inactivation by a lincosamide nucleotidyltransferase encoded by members of the lnu (previously lin) gene family (5, 34, 45). This type of resistance gene is found in staphylococci and streptococci, where it is often located on plasmids or transposons (5, 45).Lincomycin resistance in C. perfringens is relatively common, but it is usually conferred as MLS resistance by erm(B) or erm(Q) genes (10, 11). Recent studies have shown that there has been an increase in lincomycin resistance in C. perfringens strains isolated from chickens in Belgium (28). The researchers reported two strains that conferred resistance to lincomycin and carried the lnu(A) or lnu(B) gene, the first such strains reported for C. perfringens.In the current study we analyzed several multiply antibiotic-resistant isolates of C. perfringens and identified strains that were lincomycin resistant but were susceptible to erythromycin. We characterized these isolates and their lincomycin resistance determinant(s) and showed that resistance could be transferred to other C. perfringens isolates. Detailed analysis of the lincomycin-resistant strain 95-949 showed that resistance was encoded by the lnuP gene, which was located on a transposable genetic element, tISCpe8, that was located on a conjugative plasmid, pJIR2774. This plasmid is the first conjugative C. perfringens R-plasmid to be identified that does not confer tetracycline resistance. 相似文献
525.
KA Hyndman DH Evans 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2009,152(1):58-65
We recently determined that rapid changes in environmental salinity alter endothelin-1 (EDN1) mRNA levels in the euryhaline killifish, Fundulus heteroclitus, so we hypothesized that EDN1 may be a local regulator of gill ion transport in teleost fishes. The purpose of the present study was to examine the effects of changes in environmental salinity on the gill endothelin receptors: EDNRA, EDNRB, and EDNRC. Using quantitative real-time PCR, we determined that after a fresh water (FW) to seawater (SW) transfer, there is a two to threefold increase in gill EDNRA and EDNRB mRNA levels. Likewise, we found a two to three fold increase in gill EDNRA and EDNRB protein concentration. In addition, killifish that have acclimated to FW for 30 days had significantly lower EDNRA mRNA and protein levels than SW killifish. ENDRA were immunolocalized to the mitochondrion-rich cells of the killifish gill, suggesting that EDN1 signaling cascades may affect MRC function. EDNRB were found throughout the gill vasculature and on lamellar pillar cells. We previously immunolocalized EDN1 to the pillar cell suggesting that EDN1 acts as an autocrine signaling molecule and potentially regulates pillar cell tone and lamellar perfusion. We conclude that EDN1 is physiologically active in the teleost gill, and regulated by environmental salinity. Future functional studies examining the physiological role of this system are necessary to completely understand EDN1 in the fish gill. 相似文献
526.
McGee BK Butler MJ Pence DB Alexander JL Nissen JB Ballard WB Nicholson KL 《Journal of wildlife diseases》2006,42(2):415-420
To determine whether swift foxes (Vulpes velox) could facilitate transmission of Yersinia pestis to uninfected black-tailed prairie dog (Cynomys ludovicianus) colonies by acquiring infected fleas, ectoparasite and serologic samples were collected from swift foxes living adjacent to prairie dog towns during a 2004 plague epizootic in northwestern Texas, USA. A previous study (1999-2001) indicated that these swift foxes were infested almost exclusively with the flea Pulex irritans. Black-tailed prairie dogs examined from the study area harbored only Pulex simulans and Oropsylla hirsuta. Although P. irritans was most common, P. simulans and O. hirsuta were collected from six swift foxes and a single coyote (Canis latrans) following the plague epizootic. Thus, both of these canids could act as transport hosts (at least temporarily) of prairie dog fleas following the loss of their normal hosts during a plague die-off. All six adult swift foxes tested positive for antibodies to Y. pestis. All 107 fleas from swift foxes tested negative for Y. pestis by mouse inoculation. Although swift foxes could potentially carry Y. pestis to un-infected prairie dog colonies, we believe they play only a minor role in plague epidemiology, considering that they harbored just a few uninfected prairie dog fleas (P. simulans and O. hirsuta). 相似文献
527.
The peptidoglycan-degrading property of lysozyme is not required for bactericidal activity in vivo 总被引:2,自引:0,他引:2
Nash JA Ballard TN Weaver TE Akinbi HT 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(1):519-526
Lysozyme is an abundant, cationic antimicrobial protein that plays an important role in pulmonary host defense. Increased concentration of lysozyme in the airspaces of transgenic mice enhanced bacterial killing whereas lysozyme deficiency resulted in increased bacterial burden and morbidity. Lysozyme degrades peptidoglycan in the bacterial cell wall leading to rapid killing of Gram-positive organisms; however, this mechanism cannot account for the protective effect of lysozyme against Gram-negative bacteria. The current study was therefore designed to test the hypothesis that the catalytic activity (muramidase activity) of lysozyme is not required for bacterial killing in vivo. Substitution of serine for aspartic acid at position 53 (D53S) in mouse lysozyme M completely ablated muramidase activity. Muramidase-deficient recombinant lysozyme (LysM(D53S)) killed both Gram-positive and Gram-negative bacteria in vitro. Targeted expression of LysM(D53S) in the respiratory epithelium of wild-type (LysM(+/+)/LysM(D53S)) or lysozyme M(null) mice (LysM(-/-)/LysM(D53S)) resulted in significantly elevated lysozyme protein in the airspaces without any increase in muramidase activity. Intratracheal challenge of transgenic mice with Gram-positive or Gram-negative bacteria resulted in a significant increase in bacterial burden in LysM(-/-) mice that was completely reversed by targeted expression of LysM(D53S). These results indicate that the muramidase activity of lysozyme is not required for bacterial killing in vitro or in vivo. 相似文献
528.
Sampathkumar R Balasubramanyam M Tara C Rema M Mohan V 《Molecular and cellular biochemistry》2006,282(1-2):169-176
Objective: Although recent studies link altered cellular redox state to protein dysfunction in various disease-states, such associations
are least studied in clinical diabetes. Therefore, this study assessed the levels of reduced glutathione (GSH) and Na+/K+ ATPase activities in type 2 diabetic patients with and without microangiopathy. Methods: The study group comprised of a total of 160 subjects, which included non-diabetic healthy controls (n = 40) and type 2 diabetic patients without (n = 60) and with microangiopathy (n = 60), defined as presence of retinopathy with or without nephropathy. Erythrocyte Na+/K+ ATPase activity and GSH levels were estimated spectrophotometrically and fluorometry was used to determine the plasma thiobarbituric
acid reactive substances (TBARS) and serum advanced glycation end products (AGEs). Results: GSH levels in diabetic subjects without (4.8± 0.15 μmol/g Hb) and with microangiopathy (5.2± 0.14 μmol/g Hb) were significantly
lower (p < 0.001) compared to control subjects (6.3± 0.14 μmol/g Hb). Erythrocyte Na+/K+ ATPase activity was significantly reduced (p < 0.001) in diabetes subjects with (272± 7 nmol Pi/mg protein/h) and without microangiopathy (304 ± 8) compared to control
(374 ± 6) subjects. TBARS were significantly higher (p < 0.001) in diabetes subjects with (10.65± 0.81 nM/ml) and without microangiopathy (9.90± 0.5 nM/ml) compared to control
subjects (5.18± 0.18 nM/ml). Advanced glycation end product levels were also significantly (p < 0.001) elevated in diabetic subjects with microangiopathy (8.2± 1.8 AU) when compared to diabetes subjects without microangiopathy
(7.0± 2.0 AU) and control subjects (4.6± 1.9 AU). On multivariate regression analysis, GSH levels showed a positive association
with the Na+/K+ ATPase activity and negative association with TBARS and AGE levels. Conclusion: Hypoglutathionemia and increased oxidative stress appears to be early biochemical aberrations in diabetes, and through protein
alterations, oxidative stress and redox modifications may contribute to pathogenesis of diabetic microangiopathy. 相似文献
529.
Despite growing interest in traditional and local ecological knowledge for conservation and resource management, the role of migrant resource users is largely unexplored. Challenging many assumptions about what constitutes “local knowledge,” migrant and immigrant harvesters of non-timber forest products on the Olympic Peninsula, Washington possess useful ecological knowledge of overstory–understory relationships and how forestry practices affect understory biological and commercial production. Harvesters of salal (Gaultheria shallon), a shrub used in the multi-million dollar floral greens industry, were interviewed in Mason County, Washington in 2001–2003. Interviews revealed that harvesters possess different kinds of resource management knowledge depending on whether they are experienced harvesters or more recent newcomers to the area. These differences may also correlate with differences in their harvesting practices. Understanding how resource management knowledge differs between experienced and newcomer harvesters can inform forest managers in their efforts to develop effective management and permitting policies for floral greens and other non-timber forest resources in the Pacific Northwest of the United States.
相似文献
Heidi L. BallardEmail: |
530.
Because of its possible importance to the etiology of cystic fibrosis lung disease, the ion and water transport properties of tracheal epithelium were studied. Net liquid flux (J(V)) across porcine tracheal epithelium was measured in vitro using blue dextran as a volume probe. Luminal instillation of isosmotic sucrose solution (280 mM) induced a small net secretion of liquid (7.0 +/- 1.7 nl x cm(-2) x s(-1)), whereas luminal hyposmotic sucrose solutions (220 or 100 mM) induced substantial and significant (P < 0.05) liquid absorption (34.5 +/- 12 and 38.1 +/- 7.3 nl x cm(-2) x s(-1), respectively). When the luminal solution was normal (isosmotic) Krebs buffer, liquid was absorbed at 10.2 +/- 1.1 nl x cm(-2) x s(-1). Absorptive J(V) was abolished by 100 microM amiloride in the luminal solution and significantly reduced when the luminal solution was Na(+)-free Krebs solution. Absorptive J(V) was not significantly affected by 300 microM 5-nitro-2-(3-phenylpropylamino)benzoate or 100 microM diphenylamine-2-carboxylic acid, both cystic fibrosis transmembrane conductance regulator protein (CFTR) inhibitors, in the instillate but was significantly reduced by 60% when the luminal solution was Cl(-)-free Krebs solution. We conclude that water freely permeates porcine tracheal epithelium and that absorption of liquid is normally driven by active transcellular Na(+) transport and does not require the CFTR. 相似文献