scholarly journals Pleiotropic Effects of Statins: New Therapeutic Approaches to Chronic, Recurrent Infection by Staphylococcus aureus

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2047
Author(s):  
Melissa D. Evans ◽  
Susan A. McDowell
Keyword(s):  
Staphylococcus Aureus ◽  
Recurrent Infection ◽  
Opportunistic Pathogen ◽  
Pleiotropic Effects ◽  
In Vivo Studies ◽  
Therapeutic Approaches ◽  
Risk Of Death ◽  
New Therapeutic Approaches

An emergent approach to bacterial infection is the use of host rather than bacterial-directed strategies. This approach has the potential to improve efficacy in especially challenging infection settings, including chronic, recurrent infection due to intracellular pathogens. For nearly two decades, the pleiotropic effects of statin drugs have been examined for therapeutic usefulness beyond the treatment of hypercholesterolemia. Interest originated after retrospective studies reported decreases in the risk of death due to bacteremia or sepsis for those on a statin regimen. Although subsequent clinical trials have yielded mixed results and earlier findings have been questioned for biased study design, in vitro and in vivo studies have provided clear evidence of protective mechanisms that include immunomodulatory effects and the inhibition of host cell invasion. Ultimately, the benefits of statins in an infection setting appear to require attention to the underlying host response and to the timing of the dosage. From this examination of statin efficacy, additional novel host-directed strategies may produce adjunctive therapeutic approaches for the treatment of infection where traditional antimicrobial therapy continues to yield poor outcomes. This review focuses on the opportunistic pathogen, Staphylococcus aureus, as a proof of principle in examining the promise and limitations of statins in recalcitrant infection.

Cefotaxime and amikacin: results of in vitro and in vivo studies against Gram-negative bacteria and Staphylococcus aureus

1980 ◽  
Vol 6 (suppl A) ◽  
pp. 55-61 ◽  
Author(s):  
J. Klastersky ◽  
H. Gaya ◽  
S. H. Zinner ◽  
C. Bernard ◽  
J-C. Ryff ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
In Vivo Studies ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
And Staphylococcus Aureus

scholarly journals Arrhythmogenic Cardiomyopathy: Molecular Insights for Improved Therapeutic Design

2020 ◽  
Vol 7 (2) ◽  
pp. 21 ◽  
Author(s):  
Tyler L. Stevens ◽  
Michael J. Wallace ◽  
Mona El Refaey ◽  
Jason D. Roberts ◽  
Sara N. Koenig ◽  
...  
Keyword(s):  
Structural Changes ◽  
Mendelian Inheritance ◽  
In Vivo Studies ◽  
Arrhythmogenic Cardiomyopathy ◽  
New Therapeutic Approaches ◽  
Increased Risk ◽  
Fatty Replacement ◽  
Mechanistic Basis

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by structural and electrical cardiac abnormalities, including myocardial fibro-fatty replacement. Its pathological ventricular substrate predisposes subjects to an increased risk of sudden cardiac death (SCD). ACM is a notorious cause of SCD in young athletes, and exercise has been documented to accelerate its progression. Although the genetic culprits are not exclusively limited to the intercalated disc, the majority of ACM-linked variants reside within desmosomal genes and are transmitted via Mendelian inheritance patterns; however, penetrance is highly variable. Its natural history features an initial “concealed phase” that results in patients being vulnerable to malignant arrhythmias prior to the onset of structural changes. Lack of effective therapies that target its pathophysiology renders management of patients challenging due to its progressive nature, and has highlighted a critical need to improve our understanding of its underlying mechanistic basis. In vitro and in vivo studies have begun to unravel the molecular consequences associated with disease causing variants, including altered Wnt/β-catenin signaling. Characterization of ACM mouse models has facilitated the evaluation of new therapeutic approaches. Improved molecular insight into the condition promises to usher in novel forms of therapy that will lead to improved care at the clinical bedside.

scholarly journals The 5′ NAD Cap of RNAIII Modulates Toxin Production in Staphylococcus aureus Isolates

2019 ◽  
Vol 202 (6) ◽  
Author(s):  
Hector Gabriel Morales-Filloy ◽  
Yaqing Zhang ◽  
Gabriele Nübel ◽  
Shilpa Elizabeth George ◽  
Natalya Korn ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Secondary Structure ◽  
Quorum Sensing ◽  
Opportunistic Pathogen ◽  
Toxin Production ◽  
Dual Function ◽  
Content Type ◽  
The Stability

ABSTRACT Nicotinamide adenosine dinucleotide (NAD) has been found to be covalently attached to the 5′ ends of specific RNAs in many different organisms, but the physiological consequences of this modification are largely unknown. Here, we report the occurrence of several NAD-RNAs in the opportunistic pathogen Staphylococcus aureus. Most prominently, RNAIII, a central quorum-sensing regulator of this bacterium’s physiology, was found to be 5′ NAD capped in a range from 10 to 35%. NAD incorporation efficiency into RNAIII was found to depend in vivo on the −1 position of the P3 promoter. An increase in RNAIII’s NAD content led to a decreased expression of alpha- and delta-toxins, resulting in reduced cytotoxicity of the modified strains. These effects seem to be caused neither by changes in RNAIII’s secondary structure nor by a different translatability upon NAD attachment, as indicated by unaltered patterns in in vitro chemical probing and toeprinting experiments. Even though we did not observe any effect of this modification on RNAIII’s secondary structure or translatability in vitro, additional unidentified factors might account for the modulation of exotoxins in vivo. Ultimately, the study constitutes a step forward in the discovery of new roles of the NAD molecule in bacteria. IMPORTANCE Numerous organisms, including bacteria, are endowed with a 5′ NAD cap in specific RNAs. While the presence of the 5′ NAD cap modulates the stability of the modified RNA species, a significant biological function and phenotype have not been assigned so far. Here, we show the presence of a 5′ NAD cap in RNAIII from S. aureus, a dual-function regulatory RNA involved in quorum-sensing processes and regulation of virulence factor expression. We also demonstrate that altering the natural NAD modification ratio of RNAIII leads to a decrease in exotoxin production, thereby modulating the bacterium’s virulence. Our work unveils a new layer of regulation of RNAIII and the agr system that might be linked to the redox state of the NAD molecule in the cell.

scholarly journals Antimicrobial photodynamic therapy with fulleropyrrolidine: photoinactivation mechanism of Staphylococcus aureus, in vitro and in vivo studies

2015 ◽  
Vol 99 (9) ◽  
pp. 4031-4043 ◽  
Author(s):  
Mariusz Grinholc ◽  
Joanna Nakonieczna ◽  
Grzegorz Fila ◽  
Aleksandra Taraszkiewicz ◽  
Anna Kawiak ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Photodynamic Therapy ◽  
In Vivo Studies ◽  
Antimicrobial Photodynamic Therapy

Discovery and validation of the nuclear export protein CRM1 (XPO1) as a new target for the treatment of renal cell carcinoma (RCC).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 411-411
Author(s):  
Hiromi Inoue Wettersten ◽  
Michael Kauffman ◽  
Sharon Shacham ◽  
Yosef Landesman ◽  
Joy Yang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Nuclear Export ◽  
Human Kidney ◽  
In Vivo Studies ◽  
Tumor Growth Inhibition ◽  
Phase I Clinical Trials ◽  
New Therapeutic Approaches ◽  
Xenograft Mice

411 Background: The currently available targeted therapies for RCC have had limited success, so it is imperative to discover new therapeutic approaches for metastatic RCC. In a search for new such targets, we have identified inhibitors of CRM1 (XPO1, exportin1), the major karyopherin that mediates the export of most tumor suppressor proteins from the nucleus. To expand our initial work on the first generation of CRM1 inhibitors, we now evaluate KPT-330, an orally available Selective Inhibitor of Nuclear Export (SINE), the best tolerated among a series of CRM1 inhibitors that is currently in phase I clinical trials. Methods: The RCC cell lines (Caki-1 and 786-O) and a primary normal human kidney (NHK) cell line were treated with KPT-330, and MTT assays were performed. The cells were subjected to immunofluorescence and immunoblotting for appropriate proteins. Caki-1 xenograft mice were treated with KPT-330 for 15 days, and tumor volume was assessed. Results: KPT-330 selectively attenuated CRM1 levels and caused dose-dependent toxicity (EC50 < 1 µM) through apoptosis in all RCC cells. In untreated RCC cells, p21 was localized in the nucleus, where it likely functions as a cell cycle arrest protein, and in the cytosol, where it functions as an anti-apoptotic protein. However, in NHK cells, p21 was confined to the nucleus. KPT-330 increased p53 and p21 and confined them to the nucleus in both NHK and RCC cells. KPT-330 given orally inhibited RCC growth in xenograft mice (85.3 % inhibition, p < 0.001). Moreover, KPT-330 showed synergism with a Bcl-2 inhibitor ABT-737 in vitro, indicating the potential for combination therapy with a CRM1 inhibitor and Bcl-2 inhibitor. In vivo studies to test the combination of KPT-330 with Bcl-2 inhibitors are ongoing. Conclusions: We introduce a new therapeutic approach for RCC treatment based on the inhibition of the nuclear export of key tumor suppressors. Inhibition of CRM1 causes forced nuclear retention, and thereby activation, of several key p53-pathway proteins, leading to apoptosis in RCC cell lines in vitro and tumor growth inhibition in vivo.

Comparative Killing Kinetics of Methicillin-Resistant Staphylococcus aureus by Bacitracin or Mupirocin

1996 ◽  
Vol 17 (3) ◽  
pp. 178-180
Author(s):  
Edward K. Chapnick ◽  
Jeremy D. Gradon ◽  
Barry Kreiswirth ◽  
Larry I. Lutwick ◽  
Benjamin C. Schaffer ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Lower Cost ◽  
In Vivo Studies ◽  
Methicillin Resistant ◽  
Log Reduction ◽  
Different Strains ◽  
Time Kill ◽  
Kinetics Of

AbstractThe in vitro activities of bacitracin and mupirocin were compared for seven different strains of methicillin-resistant Staphylococcus aureus. Six of seven strains showed bacitracin minimum inhibitory concentrations (MICs) of 0.5 to 1.0 units/mL, and all seven had mupirocin MICs of 0.5 to 2 μg/mL. Time-kill studies revealed 2.6- to 4.5-log reduction in 24 hours with strains susceptible to bacitracin (4 units/mL) and 0 to 2.2 reduction with mupirocin (16 μg/mL). Bacitracin should be considered further for in vivo studies because of enhanced bacteriocidal effect and lower cost.

scholarly journals Precision-Cut Bovine Udder Slices (PCBUS) as an in-vitro-model of an early phase of infection of bovine mastitis

2020 ◽  
Author(s):  
Viviane Filor ◽  
Monique Petry ◽  
Jessica Meißner ◽  
Manfred Kietzmann
Keyword(s):  
Infectious Diseases ◽  
Early Phase ◽  
Antimicrobial Agents ◽  
Bovine Mastitis ◽  
Therapeutic Approaches ◽  
Tissue Slices ◽  
New Therapeutic Approaches ◽  
Pharmacological Interactions

Abstract Background The aim of this study was the establishment of precision-cut bovine udder slices (PCBUS) as an in-vitro-model to investigate pathophysiological processes in the early phase of mastitis in order to have the possibility to investigate new therapeutic approaches for the treatment of such udder inflammation in later studies. Furthermore, this model should contribute to substitute in-vivo-experiments. Bovine mastitis is one of the most common and costly infectious diseases in the dairy industry, which is largely associated with the use of antimicrobial agents. Given this problem of antimicrobial resistance, it is essential to step up research into bacterial infectious diseases. Thus, the transfer of the in-vitro-model of precision-cut tissue slices to the bovine udder enables broad research into new therapeutic approaches in this area and can also be used to address issues in basic research or the characterization of complex pathophysiological processes. Results A stimulation with LPS, PGN or the combination of both substances (LPS:PGN) demonstrated the ability of the PCBUS to react with a significant secretion of IL-1ß, TNF-α and PGE2. Conclusion The slices represent an instrument for investigating pharmacological interactions with udder tissue, which can be useful for studies on pharmacological questions and the understanding of complex pathophysiological processes of infection and inflammation.

scholarly journals Pleiotropic Effects of Metformin on Cancer

2018 ◽  
Vol 19 (10) ◽  
pp. 2850 ◽  
Author(s):  
Hans-Juergen Schulten
Keyword(s):  
Scientific Evidence ◽  
Cellular Level ◽  
Pleiotropic Effects ◽  
In Vivo Studies ◽  
Clinical Cancer Research ◽  
Anticancer Properties ◽  
Galega Officinalis ◽  
Anticancer Effects

Metformin (MTF) is a natural compound derived from the legume Galega officinalis. It is the first line antidiabetic drug for type 2 diabetes (T2D) treatment. One of its main antidiabetic effects results from the reduction of hepatic glucose release. First scientific evidence for the anticancer effects of MTF was found in animal research, published in 2001, and some years later a retrospective observational study provided evidence that linked MTF to reduced cancer risk in T2D patients. Its pleiotropic anticancer effects were studied in numerous in vitro and in vivo studies at the molecular and cellular level. Although the majority of these studies demonstrated that MTF is associated with certain anticancer properties, clinical studies and trials provided a mixed view on its beneficial anticancer effects. This review emphasizes the pleiotropic effects of MTF and recent progress made in MTF applications in basic, preclinical, and clinical cancer research.

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