bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mesalamine‐induced B7‐H1 expression on hepatic stellate cells attenuates autoimmune liver injury
Authors: Lee Jeong‐Hoon , Yoon Jung‐Hwan , Lee Yu‐Jeong , Yang Jong In , Kwak Min‐Sun , Cho Eun Ju , Jang Eun Sun , Yu Su Jong , Choi Dae Hee , Jung Eun Uk , Kim Hwi Young , Kim Bo Hyun , Chung Goh Eun , Kim Yoon Jun , Jang Ja‐June , Kim Chung Yong , Lee Hyo‐Suk 
Published: October 2010

Aim:  Hepatic stellate cells (HSCs) have immune regulatory functions. Mesalamine is an effective immune regulatory drug for inflammatory bowel disease. Thus, we hypothesized that mesalamine may also modulate the immune regulatory functions of HSCs. Since B7‐H1 plays a crucial role in regulating T‐cell apoptosis, we evaluated if mesalamine induces B7‐H1 expression on HSCs, and if so, whether mesalamine attenuates autoimmune liver injury in vivo.Methods:  LX‐2 cells, an immortalized human HSC cell line, and human peripheral T‐cells were used in this study. B7‐H1 expression on LX‐2 cells following mesalamine treatment was examined by using flow cytometry. Cell viability was analyzed by MTS assay. Concanavalin‐A (ConA) mice hepatitis model was used for in vivo study.Results:  Flow cytometry showed that mesalamine treatment increased the B7‐H1‐expressing LX‐2 cell fraction from 45.4% to 88.2%, of which increment is equivalent to that of positive control (29.9%, interferon γ‐treated cells). Human T‐cells incubated with LX‐2 cells showed significantly less cell viability in the presence of mesalamine than cells without mesalamine treatment (P < 0.001). Histological examination revealed that hepatic necroinflammation was significantly attenuated by mesalamine pretreatment (P = 0.019), although serum levels of aminotransferases were not significantly reduced. During the 24‐h period following ConA injection, 1 of 10 mice pretreated with mesalamine and 3 of 10 mice without pretreatment died.Conclusion:  These results demonstrate that mesalamine enhances B7‐H1 expression on HSCs, and thus, induces T‐cell apoptosis and attenuates autoimmune liver injury.
Purification and Biochemical Characterization of IMP-13 Metallo-β-Lactamase
Authors: Santella Gisela , Docquier Jean-Denis , Gutkind Gabriel , Rossolini Gian Maria , Radice Marcela 
Published: October 2010

ABSTRACT

The IMP-13 metallo-β-lactamase was overproduced in
Escherichia coli
BL21(DE3) and purified by chromatography. Analysis of kinetic parameters revealed some notable differences with other IMP-type enzymes, noteworthily a higher catalytic efficiency toward ticarcillin and piperacillin and a marked preference for imipenem over meropenem.
Regulation of
mprF
by Antisense RNA Restores Daptomycin Susceptibility to Daptomycin-Resistant Isolates of
Staphylococcus aureus
Authors: Rubio Aileen , Conrad Mary , Haselbeck Robert J. , G. C. Kedar , Brown-Driver Vickie , Finn John , Silverman Jared A. 
Published: October 2010

ABSTRACT

Mutations in
mprF
have been shown to result in reduced susceptibility to daptomycin and other cationic antibacterials. An
mprF
antisense-inducible plasmid was constructed and used to demonstrate that depletion of
mprF
can reestablish susceptibility to daptomycin. Inducing antisense to
mprF
also resulted in increased susceptibility to vancomycin and gentamicin but, paradoxically, decreased susceptibility to oxacillin. These results suggest that
mprF
mutations that reduce susceptibility to cationic antibacterials result in a gain-of-function phenotype.
Profiling the
Aspergillus fumigatus
Proteome in Response to Caspofungin
Authors: Cagas Steven E. , Jain Mohit Raja , Li Hong , Perlin David S. 
Published: October 2010

ABSTRACT

The proteomic response of
Aspergillus fumigatus
to caspofungin was evaluated by gel-free isobaric tagging for relative and absolute quantitation (iTRAQ) as a means to determine potential biomarkers of drug action. A cell fractionation approach yielding 4 subcellular compartment fractions was used to enhance the resolution of proteins for proteomic analysis. Using iTRAQ, a total of 471 unique proteins were identified in soluble and cell wall/plasma membrane fractions at 24 and 48 h of growth in rich media in a wild-type drug-susceptible strain. A total of 122 proteins showed at least a 2-fold change in relative abundance following exposure to caspofungin (CSF) at just below the minimum effective concentration (0.12 μg/ml). The largest changes were seen in the mitochondrial hypoxia response domain protein (AFUA_1G12250), the level of which decreased >16-fold in the secreted fraction, and ChiA1, the level of which decreased 12.1-fold in the cell wall/plasma membrane fraction. The level of the major allergen and cytotoxin AspF1 was also shown to decrease by 12.1-fold upon the addition of drug. A subsequent iTRAQ analysis of an echinocandin-resistant strain (fks1-S678P) was used to validate proteins specific to drug action. A total of 103 proteins in the 2 fractions tested by iTRAQ were differentially expressed in the wild-type susceptible strain but not significantly changed in the resistant strain. Of these potential biomarkers, 11 had levels that changed at least 12-fold. Microarray analysis of the susceptible strain was performed to evaluate the correlation between proteomics and genomics, with a total of 117 genes found to be changing at least 2-fold. Of these, a total of 22 proteins with significant changes identified by iTRAQ also showed significant gene expression level changes by microarray. Overall, these data have the potential to identify biomarkers that assess the relative efficacy of echinocandin drug therapy.
Immunocytochemistry for Amoxicillin and Its Use for Studying Uptake of the Drug in the Intestine, Liver, and Kidney of Rats
Authors: Fujiwara Kunio , Shin Masashi , Miyazaki Tsubasa , Maruta Yasuhiro 
Published: October 2010

ABSTRACTSpecific transport systems for penicillins have been recognized, but theirin vivorole in the context of other transporters remains unclear. We produced a serum against amoxicillin (anti-AMPC) conjugated to albumin with glutaraldehyde. The antiserum was specific for AMPC and ampicillin (ABPC) but cross-reacted weakly with cephalexin. This enabled us to develop an immunocytochemical (ICC) method for detecting the uptake of AMPC in the rat intestine, liver, and kidney. Three hours after a single oral administration of AMPC, the ICC method revealed that AMPC distributed to a high degree in the microvilli, nuclei, and cytoplasm of the absorptive epithelial cells of the intestine. AMPC distributed in the cytoplasm and nuclei of the hepatocytes in a characteristic granular morphology on the bile capillaries, and in addition, AMPC adsorption was observed on the luminal surface of the capillaries, intercalated portions, and interlobular bile ducts on the bile flow. Almost no AMPC could be detected 6 h postadministration in either the intestine or the liver. Meanwhile, in the kidney, AMPC persisted until 12 h postadministration to a high degree in the proximal tubules, especially in the S3 segment cells in the tubular lumen, in which numerous small bodies that strongly reacted with the antibody were observed. All these sites of AMPC accumulation correspond well to specific sites where certain transporter systems for penicillins occur, suggesting that AMPC is actually and actively absorbed, eliminated, or excreted at these sites, possibly through such certain penicillin transporters.
Evaluation of Hepatotoxicity with Off-Label Oral-Treatment Doses of Voriconazole for Invasive Fungal Infections
Authors: Gorski Elizabeth , Esterly John S. , Postelnick Michael , Trifilio Steven , Fotis Michael , Scheetz Marc H. 
Published: October 2010

ABSTRACT

The approved treatment dose of intravenous voriconazole is a weight-based dose of 4 mg/kg of body weight twice daily; the approved oral dosing is fixed at 200 mg twice daily. In our institution, patients frequently receive oral high-dose voriconazole at 4 mg/kg twice daily. It is unknown if higher doses are associated with increased hepatotoxicity. A retrospective cohort study of patients treated with oral voriconazole for presumed invasive fungal infection for ≥7 days was completed. Patients receiving a fixed dose (i.e., labeled dose) were frequency matched and compared to those receiving a weight-based dose (i.e., high dose). The primary endpoint of hepatotoxicity was evaluated by using NCI Common Terminology Criteria (CTC) and components of liver enzymes measuring >3× the upper limit of normal (ULN) and >5× baseline measurements. Secondary endpoints included an incidence of other adverse drug events. Twenty-five labeled-dose and 84 high-dose voriconazole patients were studied. Liver enzyme abnormalities were similar between groups, with the exception of labeled-dose patients experiencing more alkaline phosphatase (ALP) CTC >2× the baseline (
P
= 0.02) and ALP levels >3× the ULN (
P
= 0.02). Treatment with high dose was associated with the discontinuation of voriconazole for practitioner attribution of adverse drug events (
P
= 0.03), although reasons varied and no commonality of biomarker abnormality was identified. Multivariate analysis revealed that the duration of therapy and higher mg/kg total daily doses as interval variables were predictive of some hepatotoxicity outcomes. No difference existed in liver abnormalities for high-dose voriconazole; however, higher mg/kg doses and a longer duration of therapy may be associated with hepatotoxicity.
Interleukin-1 Receptor Signaling Is Required To Overcome the Effects of Pertussis Toxin and for Efficient Infection- or Vaccination-Induced Immunity against
Bordetella pertussis
Authors: Zhang Xuqing , Hester Sara E. , Kennett Mary J. , Karanikas Alexia T. , Bendor Liron , Place David E. , Harvill Eric T. 
Published: October 2010

ABSTRACT

Interleukin-1 receptor-deficient (IL-1R
−/−
) mice are healthy despite being colonized by commensal microbes but are defective in defenses against specific pathogens, suggesting that IL-1R-mediated effects contribute to immune responses against specific pathogenic mechanisms. To better define the role of IL-1R in immunity to respiratory infections, we challenged IL-1R
−/−
mice with
Bordetella pertussis
and
Bordetella parapertussis
, the causative agents of whooping cough. Following inoculation with
B. pertussis
, but not
B. parapertussis
, IL-1R
−/−
mice showed elevated bacterial numbers and more extensive inflammatory pathology than wild-type mice. Acellular
B. pertussis
vaccines were not efficiently protective against
B. pertussis
in IL-1R
−/−
mice.
B. pertussis
-stimulated dendritic cells from IL-1R
−/−
mice produced higher levels of tumor necrosis factor alpha (TNF-α) and IL-6 than wild-type cells. Moreover, elevated levels of gamma interferon (IFN-γ) and TNF-α but lower levels of IL-10 were detected during
B. pertussis
infection in IL-1R
−/−
mice. Since
B. parapertussis
did not cause severe disease in IL-1R
−/−
mice, we hypothesized that the extreme requirement for IL-1R involves pertussis toxin (Ptx), which is expressed only by
B. pertussis
. An isogenic Ptx-deficient
B. pertussis
strain had only a modest phenotype in wild-type mice but was completely defective in causing lethal disease in IL-1R
−/−
mice, indicating that the particular virulence of
B. pertussis
in these mice requires Ptx. Ptx contributes to IL-1β induction by
B. pertussis
, which is involved in IL-10 induction through IL-1R signaling. IL-10 treatment reduced
B. pertussis
numbers in IL-1R
−/−
mice, suggesting that the lower IL-10 responses partially account for the uncontrolled inflammation and bacterial growth in these mice.
Lipoproteins of Bacterial Pathogens
Authors: Kovacs-Simon A. , Titball R. W. , Michell S. L. 
Published: October 2010

ABSTRACTBacterial lipoproteins are a set of membrane proteins with many different functions. Due to this broad-ranging functionality, these proteins have a considerable significance in many phenomena, from cellular physiology through cell division and virulence. Here we give a general overview of lipoprotein biogenesis and highlight examples of the roles of lipoproteins in bacterial disease caused by a selection of medically relevant Gram-negative and Gram-positive pathogens:Mycobacterium tuberculosis,Streptococcus pneumoniae,Borrelia burgdorferi, andNeisseria meningitidis. Lipoproteins have been shown to play key roles in adhesion to host cells, modulation of inflammatory processes, and translocation of virulence factors into host cells. As such, a number of lipoproteins have been shown to be potential vaccines. This review provides a summary of some of the reported roles of lipoproteins and of how this knowledge has been exploited in some cases for the generation of novel countermeasures to bacterial diseases.
Exposure to Cigarette Smoke Inhibits the Pulmonary T-Cell Response to Influenza Virus andMycobacterium tuberculosis
Authors: Feng Yan , Kong Ying , Barnes Peter F. , Huang Fang-Fang , Klucar Peter , Wang Xisheng , Samten Buka , Sengupta Mayami , Machona Bruce , Donis Ruben , Tvinnereim Amy R. , Shams Homayoun 
Published: October 2010

ABSTRACTSmoking is associated with increased susceptibility to tuberculosis and influenza. However, little information is available on the mechanisms underlying this increased susceptibility. Mice were left unexposed or were exposed to cigarette smoke and then infected withMycobacterium tuberculosisby aerosol or influenza A by intranasal infection. Some mice were given a DNA vaccine encoding an immunogenicM. tuberculosisprotein. Gamma interferon (IFN-γ) production by T cells from the lungs and spleens was measured. Cigarette smoke exposure inhibited the lung T-cell production of IFN-γ during stimulationin vitrowith anti-CD3, after vaccination with a construct expressing an immunogenic mycobacterial protein, and during infection withM. tuberculosisand influenza A virusin vivo. Reduced IFN-γ production was mediated through the decreased phosphorylation of transcription factors that positively regulate IFN-γ expression. Cigarette smoke exposure increased the bacterial burden in mice infected withM. tuberculosisand increased weight loss and mortality in mice infected with influenza virus. This study provides the first demonstration that cigarette smoke exposure directly inhibits the pulmonary T-cell response toM. tuberculosisand influenza virus in a physiologically relevant animal model, increasing susceptibility to both pathogens.
Identification of a Genetic Locus Responsible for Antimicrobial Peptide Resistance in
Clostridium difficile
Authors: McBride Shonna M. , Sonenshein Abraham L. 
Published: October 2010

ABSTRACT

Clostridium difficile
causes chronic intestinal disease, yet little is understood about how the bacterium interacts with and survives in the host. To colonize the intestine and cause persistent disease, the bacterium must circumvent killing by host innate immune factors, such as cationic antimicrobial peptides (CAMPs). In this study, we investigated the effect of model CAMPs on growth and found that
C. difficile
is not only sensitive to these compounds but also responds to low levels of CAMPs by expressing genes that lead to CAMP resistance. By plating the bacterium on medium containing the CAMP nisin, we isolated a mutant capable of growing in three times the inhibitory concentration of CAMPs. This mutant also showed increased resistance to the CAMPs gallidermin and polymyxin B, demonstrating tolerance to different types of antimicrobial peptides. We identified the mutated gene responsible for the resistance phenotype as CD1352. This gene encodes a putative orphan histidine kinase that lies adjacent to a predicted ABC transporter operon (CD1349 to CD1351). Transcriptional analysis of the ABC transporter genes revealed that this operon was upregulated in the presence of nisin in wild-type cells and was more highly expressed in the CD1352 mutant. The insertional disruption of the CD1349 gene resulted in significant decreases in resistance to the CAMPs nisin and gallidermin but not polymyxin B. Because of their role in cationic antimicrobial peptide resistance, we propose the designation
cprABC
for genes CD1349 to CD1351 and
cprK
for the CD1352 gene. These results provide the first evidence of a
C. difficile
gene associated with antimicrobial peptide resistance.
Vaccination with Outer Membrane Complexes Elicits Rapid Protective Immunity to Multidrug-Resistant
Acinetobacter baumannii
Authors: McConnell Michael J. , Domínguez-Herrera Juan , Smani Younes , López-Rojas Rafael , Docobo-Pérez Fernando , Pachón Jerónimo 
Published: October 2010

ABSTRACT

Acinetobacter baumannii
causes pneumonias, bacteremias, and skin and soft tissue infections, primarily in the hospitalized setting. The incidence of infections caused by
A. baumannii
has increased dramatically over the last 30 years, while at the same time the treatment of these infections has been complicated by the emergence of antibiotic-resistant strains. Despite these trends, no vaccines or antibody-based therapies have been developed for the prevention of
A. baumannii
infection. In this study, an outer membrane complex vaccine consisting of multiple surface antigens from the bacterial membrane of
A. baumannii
was developed and tested in a murine sepsis model. Immunization elicited humoral and cellular responses that were able to reduce postinfection bacterial loads, reduce postinfection proinflammatory cytokine levels in serum, and protect mice from infection with human clinical isolates of
A. baumannii
. A single administration of the vaccine was able to elicit protective immunity in as few as 6 days postimmunization. In addition, vaccine antiserum was used successfully to therapeutically rescue naïve mice with established infection. These results indicate that prophylactic vaccination and antibody-based therapies based on an outer membrane complex vaccine may be viable approaches to preventing the morbidity and mortality caused by this pathogen.
Mycobacterium
ulcerans
Triggers T-Cell Immunity followed by Local and Regional but Not Systemic Immunosuppression
Authors: Fraga Alexandra G. , Cruz Andrea , Martins Teresa G. , Torrado Egídio , Saraiva Margarida , Pereira Daniela R. , Meyers Wayne M. , Portaels Françoise , Silva Manuel T. , Castro António G. , Pedrosa Jorge 
Published: October 2010

ABSTRACT

Buruli ulcer is a neglected infectious disease caused by
Mycobacterium ulcerans
and is characterized by necrotic cutaneous lesions induced by the exotoxin mycolactone. Despite evidence of Th1-mediated protective immunity,
M. ulcerans
infection has been associated with systemic immunosuppression. We show that early during mouse infection with either mycolactone-positive or negative strains, pathogen-specific gamma interferon (IFN-γ)-producing T cells developed in the draining lymph node (DLN). CD4
+
cells migrated to the infection foci, but progressive infection with virulent
M. ulcerans
led to the local depletion of recruited cells. Moreover, dissemination of virulent
M. ulcerans
to the DLN was accompanied by extensive DLN apoptotic cytopathology, leading to depletion of CD4
+
T cells and abrogation of IFN-γ expression. Advanced footpad infection with virulent
M. ulcerans
did not induce increased susceptibility to systemic coinfection by
Listeria monocytogenes
. These results show that infection with
M. ulcerans
efficiently triggers a mycobacterium-specific T-cell response in the DLN and that progression of infection with highly virulent
M. ulcerans
leads to a local and regional suppression of that immune response, but without induction of systemic immunosuppression. These results suggest that prophylactic and/or therapeutic interventions to prevent dissemination of
M. ulcerans
to DLN during the early phase of infection would contribute for the maintenance of protective immunity and disease control.
Probiotic
Lactobacillus reuteri
Ameliorates Disease Due to Enterohemorrhagic
Escherichia coli
in Germfree Mice
Authors: Eaton Kathryn A. , Honkala Alexander , Auchtung Thomas A. , Britton Robert A. 
Published: October 2010

ABSTRACT

Strains of enterohemorrhagic
Escherichia coli
(EHEC) are a group of Shiga toxin-producing food-borne pathogens that cause severe hemorrhagic colitis and can lead to hemolytic-uremic syndrome (HUS), a life-threatening condition that principally affects children and for which there is no effective treatment. We used a germfree mouse model of renal and enteric disease due to EHEC to determine if probiotic
Lactobacillus reuteri
ATCC PTA 6475 is effective in suppressing disease symptoms caused by EHEC. When germfree Swiss Webster mice are monocolonized with EHEC, they develop disease characterized by weight loss, cecal luminal fluid accumulation, and renal tubular necrosis. When
L. reuteri
was administered 1 day prior to EHEC challenge and every other day thereafter, EHEC colonization was suppressed and mice were significantly protected from the manifestations of disease. Protection from disease did not require the induction of the antimicrobial compound reuterin in
L. reuteri
prior to treatment. The twice-daily administration of
L. reuteri
appeared more effective than every-other-day administration. These data indicated that
L. reuteri
partially protects mice from disease manifestations of EHEC.
MyD88-Dependent Signaling Protects against Anthrax Lethal Toxin-Induced Impairment of Intestinal Barrier Function
Authors: Okugawa Shu , Moayeri Mahtab , Eckhaus Michael A. , Crown Devorah , Miller-Randolph Sharmina , Liu Shihui , Akira Shizuo , Leppla Stephen H. 
Published: October 2010

ABSTRACT

MyD88-deficient mice were previously shown to have increased susceptibility to
Bacillus anthracis
infection relative to wild-type animals. To determine the mechanism by which MyD88 protects against
B. anthracis
infection, knockout mice were challenged with nonencapsulated, toxigenic
B. anthracis
or with anthrax toxins. MyD88-deficient mice had increased susceptibility to
B. anthracis
and anthrax lethal toxin but not to edema toxin. Lethal toxin alone induced marked multifocal intestinal ulcers in the knockout animals, compromising the intestinal epithelial barrier. The resulting enteric bacterial leakage in the knockout animals led to peritonitis and septicemia. Focal ulcers and erosion were also found in MyD88-heterozygous control mice but with far lower incidence and severity.
B. anthracis
infection also induced a similar enteric bacterial septicemia in MyD88-deficient mice but not in heterozygous controls. We show that lethal toxin and
B. anthracis
challenge induce bacteremia as a result of intestinal damage in MyD88-deficient mice. These results suggest that loss of the intestinal epithelial barrier and enteric bacterial septicemia may contribute to sensitizing MyD88-deficient mice to
B. anthracis
and that MyD88 plays a protective role against lethal toxin-induced impairment of intestinal barrier.