scholarly journals gC1qR/p33 Blockade Reduces Staphylococcus aureus Colonization of Target Tissues in an Animal Model of Infective Endocarditis

2006 ◽  
Vol 74 (8) ◽  
pp. 4418-4423 ◽  
Author(s):  
Ellinor I. B. Peerschke ◽  
Arnold S. Bayer ◽  
Berhane Ghebrehiwet ◽  
Yan Q. Xiong
Keyword(s):  
Staphylococcus Aureus ◽  
Infective Endocarditis ◽  
Inflammatory Responses ◽  
Bacterial Colonization ◽  
Statistical Significance ◽  
Serum Levels ◽  
Cellular Protein ◽  
Prophylaxis Therapy

ABSTRACT gC1qR/p33 (gC1qR) is a ubiquitously expressed cellular protein that is also found in plasma and the extracellular matrix. In addition to its role in modulating the activation of complement and kinin cascades, gC1qR has been identified as a putative host ligand for endovascular pathogens, including Staphylococcus aureus. The present study provides evidence of the ability of soluble gC1qR to enhance S. aureus-fibrinogen interactions via simultaneously binding fibrinogen and S. aureus. This interaction was inhibited in vitro by two monoclonal antibodies (MAbs 74.5.2 and 60.11) recognizing distinct structural and functional domains of gC1qR. To evaluate the in vivo role of gC1qR, MAbs 74.5.2 and 60.11 were used in an experimental rat model of S. aureus endocarditis. Each MAb (100 mg/kg of body weight, given intraperitoneally) reached sustained (>60 h) and high (100 to 200 μg/ml) serum levels. Prophylaxis with MAb 60.11 or 74.5.2 caused substantial reductions in S. aureus colonization of aortic valves, kidneys, and the spleen compared to untreated controls. However, only MAb 74.5.2 prophylaxis therapy reached statistical significance, and only sera from animals protected with MAb 74.5.2 inhibited gC1qR-mediated S. aureus interactions with fibrinogen. Although not statistically significant, the reductions in bacterial colonization achieved with MAb 60.11 alone and in combination with MAb 74.5.2 (versus MAb 74.5.2 alone) suggest that there are effects of gC1qR blockade on S. aureus infective endocarditis in addition to blocking gC1qR-mediated S. aureus binding to fibrinogen. Such impacts may include direct modulation of complement (MAb 60.11) and kinin cascades (MAb 74.5.2) and/or activation of immune and inflammatory responses via localized immune complex formation.

scholarly journals In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and in Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 615
Author(s):  
Shang-En Huang ◽  
Erna Sulistyowati ◽  
Yu-Ying Chao ◽  
Bin-Nan Wu ◽  
Zen-Kong Dai ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Antioxidant Properties ◽  
Serum Levels ◽  
Gene Expressions ◽  
Tnf Α ◽  
Anti Inflammatory

Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA.

scholarly journals A Niclosamide-releasing hot-melt extruded catheter prevents Staphylococcus aureus experimental biomaterial-associated infection

2022 ◽  
Author(s):  
Jesus Augusto Vazquez-Rodriguez ◽  
Bahaa Shaqour ◽  
Clara Guarch-Perez ◽  
Emilia Choinska ◽  
Martijn Riool ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mouse Model ◽  
Bacterial Colonization ◽  
Thermoplastic Polyurethane ◽  
In Vitro Models ◽  
Surrounding Tissue ◽  
Preclinical Development ◽  
Hot Melt

Biomaterial-associated infections are a major healthcare challenge as they are responsible for high disease burden in critically ill patients. In this study, we have developed drug-eluting antibacterial catheters to prevent catheter-related infections. Niclosamide (NIC), originally a well-studied antiparasitic drug, was incorporated into the polymeric matrix of thermoplastic polyurethane (TPU) via solvent casting, and catheters were fabricated using hot-melt extrusion technology. The mechanical and physicochemical properties of TPU polymers loaded with NIC were studied. NIC was released in a sustained manner from the catheters and exhibited antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis in different in vitro models. Moreover, the antibacterial efficacy of NIC-loaded catheters was validated in an in vivo biomaterial-associated infection mouse model using a methicillin-susceptible and methicillin-resistant strain of S. aureus. The released NIC from the produced catheters reduced bacterial colonization of the catheter as well as of the surrounding tissue. A sustained in vivo release of NIC from the catheters for at least 14 days was observed. In summary, the NIC-releasing hot-melt extruded catheters prevented implant colonization and reduced the bacterial colonization of peri-catheter tissue by methicillin sensitive as well as resistant S. aureus in a biomaterial-associated infection mouse model and has good prospects for preclinical development.

scholarly journals Glycyrrhizin Protects Rats from Sepsis by Blocking HMGB1 Signaling

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Feng Zhao ◽  
Yong Fang ◽  
Shuixiang Deng ◽  
Xiantao Li ◽  
Yun Zhou ◽  
...  
Keyword(s):  
Cell Surface ◽  
Proinflammatory Cytokines ◽  
Inflammatory Mediator ◽  
Inflammatory Responses ◽  
Serum Levels ◽  
Direct Stimulation ◽  
Potential Therapeutic Target ◽  
Surface Receptors

Background. HMGB1 acts as an important inflammatory mediator and is a potential therapeutic target for sepsis. Glycyrrhizin (GL), a natural triterpene glycoside derived from licorice, has been demonstrated to inhibit HMGB1 activity. The aim of this study is to explore how GL affects the HMGB1 signaling in sepsis. Methods. We used a CLP model of sepsis and in vitro LPS or HMGB1-treated NR8383 cells to examine the effects of GL on expression of HMGB1 and proinflammatory cytokines. Furthermore, we explored the effect of GL on interactions between HMGB1 and RAGE or TLR4 and the activations of NF-κB and MAPKs. Results. GL significantly decreased mortality and reduced serum levels of HMGB1 in vivo. GL also attenuated the release and expression of HMGB1 and proinflammatory cytokines. Direct stimulation by HMGB1 elevated the release of proinflammatory cytokines faster than LPS did and it was also inhibited by GL. Furthermore, GL blocked the interaction of HMGB1 with RAGE and TLR4 and suppressed the downstream MAPKs/NF-κB signaling pathway. Conclusion. GL may protect rats against sepsis by blocking the interaction of HMGB1 with cell surface receptors and HMGB1-mediated inflammatory responses.

scholarly journals 3′,5′-Cyclic Diguanylic Acid Reduces the Virulence of Biofilm-Forming Staphylococcus aureus Strains in a Mouse Model of Mastitis Infection

2005 ◽  
Vol 49 (8) ◽  
pp. 3109-3113 ◽  
Author(s):  
Eric Brouillette ◽  
Mamoru Hyodo ◽  
Yoshihiro Hayakawa ◽  
David K. R. Karaolis ◽  
François Malouin
Keyword(s):  
Staphylococcus Aureus ◽  
Mouse Model ◽  
Bacterial Colonization ◽  
Dependent Manner ◽  
Signaling Systems ◽  
Cyclic Dinucleotides ◽  
Novel Drug ◽  
Dose Dependent

ABSTRACT The cyclic dinucleotide 3′,5′-cyclic diguanylic acid (c-di-GMP) is a naturally occurring small molecule that regulates important signaling systems in bacteria. We have recently shown that c-di-GMP inhibits Staphylococcus aureus biofilm formation in vitro and its adherence to HeLa cells. We now report that c-di-GMP treatment has an antimicrobial and antipathogenic activity in vivo and reduces, in a dose-dependent manner, bacterial colonization by biofilm-forming S. aureus strains in a mouse model of mastitis infection. Intramammary injections of 5 and 50 nmol of c-di-GMP decreased colonization (bacterial CFU per gram of gland) by 0.79 (P > 0.05) and 1.44 (P < 0.01) logs, respectively, whereas 200-nmol doses allowed clearance of the bacteria below the detection limit with a reduction of more than 4 logs (P < 0.001) compared to the untreated control groups. These results indicate that cyclic dinucleotides potentially represent an attractive and novel drug platform which could be used alone or in combination with other agents or drugs in the prevention, treatment, or control of infection.

scholarly journals Identification of Streptococcus sanguinis Genes Required for Biofilm Formation and Examination of Their Role in Endocarditis Virulence

2008 ◽  
Vol 76 (6) ◽  
pp. 2551-2559 ◽  
Author(s):  
Xiuchun Ge ◽  
Todd Kitten ◽  
Zhenming Chen ◽  
Sehmi P. Lee ◽  
Cindy L. Munro ◽  
...  
Keyword(s):  
Infective Endocarditis ◽  
Dental Plaque ◽  
Biofilm Formation ◽  
Bacterial Colonization ◽  
Abundant Species ◽  
Oral Biofilm ◽  
Streptococcus Sanguinis ◽  
Streptococcal Species

ABSTRACT Streptococcus sanguinis is one of the pioneers in the bacterial colonization of teeth and is one of the most abundant species in the oral biofilm called dental plaque. S. sanguinis is also the most common viridans group streptococcal species implicated in infective endocarditis. To investigate the association of biofilm and endocarditis, we established a biofilm assay and examined biofilm formation with a signature-tagged mutagenesis library of S. sanguinis. Four genes that have not previously been associated with biofilm formation in any other bacterium, purB, purL, thrB, and pyrE, were putatively identified as contributing to in vitro biofilm formation in S. sanguinis. By examining 800 mutants for attenuation in the rabbit endocarditis model and for reduction in biofilm formation in vitro, we found some mutants that were both biofilm defective and attenuated for endocarditis. However, we also identified mutants with only reduced biofilm formation or with only attenuation in the endocarditis model. This result indicates that the ability to form biofilms in vitro is not associated with endocarditis virulence in vivo in S. sanguinis.

scholarly journals Celery (Apium graveolens) as a potential antibacterial agent and its effect on cytokeratin-17 and other healing promoters in skin wounds infected with methicillin-resistant Staphylococcus aureus

2020 ◽  
Vol 13 (5) ◽  
pp. 865-871
Author(s):  
Yos Adi Prakoso ◽  
Chylen Setiyo Rini ◽  
Asih Rahayu ◽  
Miarsono Sigit ◽  
Dyah Widhowati
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Colonization ◽  
Negative Control Group ◽  
Negative Control ◽  
Apium Graveolens ◽  
Control Group ◽  
Sprague Dawley ◽  
Methicillin Resistant

Background and Aim: Antimicrobial resistance is a global problem caused by extensive utilization of antibiotics that promote gene resistant among bacteria, including Staphylococcus aureus. This study aimed to analyze the potential effects of celery (Apium graveolens) extract as an antioxidant and antimicrobial agent against methicillin-resistant S. aureus (MRSA), in vitro and in vivo. Materials and Methods: Celery was extracted and tested against a MRSA isolate in vitro. The minimum inhibitory concentration (MIC) against MRSA for the celery extract (CE) was determined to be 0.1% and it was formulated into a cream. A total of 30 female Sprague Dawley rats were divided into five groups: Group 1, negative control; Group 2, positive control; Group 3, treated with 0.05% CE cream; Group 4, 0.1% CE cream; and Group 5, 0.2% CE cream. All animals in the groups were exposed to a full-thickness skin biopsy on the dorsal portion, and they were infected with 30 μL of 105 colony-forming units of the MRSA isolate. The treatment was administered twice a day for 7 days. The skin samples were collected on days 3 and 7 after the treatment. The skin tissue was examined histologically using hematoxylin and eosin, Gram staining, and immunohistochemistry against cytokeratin (CK)-17. Results: Results showed that 0.2% of CE cream was the best treatment for wounds infected with MRSA. CE (0.2%) cream increased skin reepithelialization, fibroblast proliferation, and CK-17 expression; it also decreased the percentage of wound area, inflammatory cell infiltration, and bacterial colonization in skin wound tissue compared to the other treatments (p≤0.05). Conclusion: This study demonstrated that celery could be utilized as an alternative herbal therapy against MRSA-associated skin infections.

scholarly journals Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents.

1991 ◽  
Vol 173 (4) ◽  
pp. 1021-1024 ◽  
Author(s):  
G D Martich ◽  
R L Danner ◽  
M Ceska ◽  
A F Suffredini
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Inflammatory Responses ◽  
Statistical Significance ◽  
Interleukin 8 ◽  
Necrosis Factor Alpha ◽  
Normal Humans ◽  
Necrosis Factor

Interleukin 8 (IL-8), a potent activator of neutrophils, may be important in the early host response to serious Gram-negative infections. IL-8 was measured with other acute phase cytokines (tumor necrosis factor alpha [TNF-alpha], IL-6 and IL-1 beta) in 25 normal humans randomized to receive either intravenous endotoxin alone or endotoxin after oral administration of ibuprofen or pentoxifylline, agents that alter some of the inflammatory responses induced by endotoxin in vitro. TNF immunoreactivity was maximum at 1.5 h, and total TNF (area under the curve) was 4.2- and 4.5-fold greater in subjects given endotoxin/ibuprofen compared to subjects given endotoxin alone (p = 0.026) or endotoxin/pentoxifylline (p = 0.004), respectively. IL-6 levels were maximum at 2-3 h and did not differ among the three groups. No IL-1 beta was detected in any subject. IL-8 levels peaked at 2 h in subjects given either endotoxin alone or endotoxin/pentoxifylline, falling towards baseline by 5 h. Subjects given endotoxin/ibuprofen had a more sustained rise in IL-8 with peak levels 2.8- and 2.5-fold higher at 3 h compared to endotoxin alone (p = 0.048) or endotoxin/pentoxifylline (p = 0.023), respectively. Differences in total IL-8 release among groups approached statistical significance (ANOVA, p = 0.07). This trend reflected the increased release of IL-8 by the subjects receiving ibuprofen compared to pentoxifylline (1.9-fold higher; p = 0.024). This suggests that cyclooxygenase products may provide important negative feedback loops for cytokine production in vivo. Increases in circulating IL-8 are part of the acute inflammatory response of humans to endotoxin. Altered cytokine responses caused by antiinflammatory therapy may have important implications for both host defense and injury during septicemia.

scholarly journals Synergistic Activity of Ceftobiprole and Vancomycin in a Rat Model of Infective Endocarditis Caused by Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus

2012 ◽  
Vol 56 (3) ◽  
pp. 1476-1484 ◽  
Author(s):  
Jeffrey Fernandez ◽  
Darren Abbanat ◽  
Wenchi Shang ◽  
Wenping He ◽  
Karen Amsler ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Infective Endocarditis ◽  
Rat Model ◽  
Synergistic Effects ◽  
Synergistic Activity ◽  
Methicillin Resistant ◽  
Content Type ◽  
Cell Densities

ABSTRACTThe therapeutic activity of ceftobiprole medocaril, the prodrug of ceftobiprole, was compared to that of vancomycin, daptomycin, and the combination of a subtherapeutic dose of ceftobiprole and vancomycin in a rat model of infective endocarditis due to methicillin-resistantStaphylococcus aureus(MRSA) (ATCC 43300) or glycopeptide-intermediateStaphylococcus aureus(GISA) (NRS4 and HIP 5836) strains. The minimum bactericidal concentrations of ceftobiprole, vancomycin, and daptomycin at bacterial cell densities similar to those encountered in the cardiac vegetation in the rat endocarditis model were 2, >64, and 8 μg/ml, respectively, for MRSA ATCC 43300 and 4, >64, and 8 μg/ml, respectively, for the GISA strain. Ceftobiprole medocaril administered in doses of 100 mg/kg of body weight given intravenously (i.v.) twice a day (BID) every 8 h (q8h) (equivalent to a human therapeutic dose of ceftobiprole [500 mg given three times a day [TID]) was the most effective monotherapy, eradicating nearly 5 log10CFU/g MRSA or 6 log10CFU/g GISA organisms from the cardiac vegetation and had the highest incidence of sterile vegetation compared to the other monotherapies in the endocarditis model. Inin vitrotime-kill studies, synergistic effects were observed with ceftobiprole and vancomycin on MRSA and GISA strains, andin vivosynergy was noted with combinations of subtherapeutic doses of these agents for the same strains. Additionally, sterile vegetations were achieved in 33 and 60%, respectively, of the animals infected with MRSA ATCC 43300 or GISA NRS4 receiving ceftobiprole-vancomycin combination therapy. In summary, ceftobiprole was efficacious both as monotherapy and in combination with vancomycin in treating MRSA and GISA infections in a rat infective endocarditis model and warrants further evaluation.

scholarly journals In-vitro and in-vivo metabolism of different aspirin formulations studied by a validated liquid chromatography tandem mass spectrometry method

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michele Dei Cas ◽  
Jessica Rizzo ◽  
Mariangela Scavone ◽  
Eti Femia ◽  
Gian Marco Podda ◽  
...  
Keyword(s):  
Oral Administration ◽  
Whole Blood ◽  
Serum Levels ◽  
Reversed Phase ◽  
Weekly Treatment ◽  
Low Dose Aspirin ◽  
Liquid Chromatography Tandem Mass ◽  
Enteric Coated

AbstractLow-dose aspirin (ASA) is used to prevent cardiovascular events. The most commonly used formulation is enteric-coated ASA (EC-ASA) that may be absorbed more slowly and less efficiently in some patients. To uncover these “non-responders” patients, the availability of proper analytical methods is pivotal in order to study the pharmacodynamics, the pharmacokinetics and the metabolic fate of ASA. We validated a high-throughput, isocratic reversed-phase, negative MRM, LC–MS/MS method useful for measuring circulating ASA and salicylic acid (SA) in blood and plasma. ASA-d4 and SA-d4 were used as internal standards. The method was applied to evaluate: (a) the "in vitro" ASA degradation by esterases in whole blood and plasma, as a function of time and concentration; (b) the "in vivo" kinetics of ASA and SA after 7 days of oral administration of EC-ASA or plain-ASA (100 mg) in healthy volunteers (three men and three women, 37–63 years). Parameters of esterases activity were Vmax 6.5 ± 1.9 and Km 147.5 ± 64.4 in plasma, and Vmax 108.1 ± 20.8 and Km 803.2 ± 170.7 in whole blood. After oral administration of the two formulations, tmax varied between 3 and 6 h for EC-ASA and between 0.5 and 1.0 h for plain-ASA. Higher between-subjects variability was seen after EC-ASA, and one subject had a delayed absorption over eight hours. Plasma AUC was 725.5 (89.8–1222) for EC-ASA, and 823.1(624–1196) ng h/mL (median, 25–75% CI) for plain ASA. After the weekly treatment, serum levels of TxB2 were very low (< 10 ng/mL at 24 h from the drug intake) in all the studied subjects, regardless of the formulation or the tmax. This method proved to be suitable for studies on aspirin responsiveness.

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