Celecoxib Enhances the Efficacy of Low-Dose Antibiotic Treatment against Polymicrobial Sepsis in Mice and Clinical Isolates of ESKAPE Pathogens

Annamanedi, Madhavi; Varma, Gajapati Y. N.; Anuradha, K.; Kalle, Arunasree M.

doi:10.3389/fmicb.2017.00805

Cited by 16 publications

(12 citation statements)

References 53 publications

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“…SIRT1/Akt/NF-κB signaling can play an anti-inflammatory role in asthma, while SIRT1/HIF-1α signaling exhibits a pro-inflammatory effect ( 62 ). In addition, SIRT1/TAK1 and SIRT1/Bax pathways are implicated in tuberculosis ( 63 ), SIRT1/COX-2 signaling is involved in the development of bacterial pneumonia ( 64 ), and SIRT1/MAPK signaling is important in regulating lung cancer progression ( 65 ) ( Fig. 3 ).…”

Section: Downstream Pathways and Mechanisms Through Hmgb1mentioning

confidence: 99%

“…Recent studies have shown that SIRT1 plays an important role in infection and inflammation ( 107 108 ). Previous in vivo and in vitro studies have demonstrated that celecoxib, a non-antibiotic agent, induced SIRT1 expression, which controlled the expressions of COX-2 and NF-κB, thus causing decreased expressions of pro-inflammatory cytokines ( 64 ). Similar effects were shown in a study on the effect of the SRT3025 compound (a SIRT1 activator) in treating pneumococcal pneumonia.…”

Section: Multitasking Roles In Respiratory Diseasesmentioning

confidence: 99%

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As a Modulator, Multitasking Roles of SIRT1 in Respiratory Diseases

2022

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As far the current severe coronavirus disease 2019 (COVID-19), respiratory disease is still the biggest threat to human health. In addition, infectious respiratory diseases are particularly prominent. In addition to killing and clearing the infection pathogen directly, regulating the immune responses against the pathogens is also an important therapeutic modality. Sirtuins belong to NAD+-dependent class III histone deacetylases. Among 7 types of sirtuins, silent information regulator type-1 (SIRT1) played a multitasking role in modulating a wide range of physiological processes, including oxidative stress, inflammation, cell apoptosis, autophagy, antibacterial and antiviral functions. It showed a critical effect in regulating immune responses by deacetylation modification, especially through high-mobility group box 1 (HMGB1), a core molecule regulating the immune system. SIRT1 was associated with many respiratory diseases, including COVID-19 infection, bacterial pneumonia, tuberculosis, and so on. Here, we reviewed the latest research progress regarding the effects of SIRT1 on immune system in respiratory diseases. First, the structure and catalytic characteristics of SIRT1 were introduced. Next, the roles of SIRT1, and the mechanisms underlying the immune regulatory effect through HMGB1, as well as the specific activators/inhibitors of SIRT1, were elaborated. Finally, the multitasking roles of SIRT1 in several respiratory diseases were discussed separately. Taken together, this review implied that SIRT1 could serve as a promising specific therapeutic target for the treatment of respiratory diseases.

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Section: Downstream Pathways and Mechanisms Through Hmgb1mentioning

confidence: 99%

Section: Multitasking Roles In Respiratory Diseasesmentioning

confidence: 99%

As a Modulator, Multitasking Roles of SIRT1 in Respiratory Diseases

2022

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“…Other examples include the use of a combination of cephalosporin antibiotic with diazabicyclooctane (a non-β-lactamase inhibitor) to restore susceptibility of extended-spectrum β-lactamases (ESBLs) producing E. coli and K. pneumoniae strains 8. In another approach, combination of ampicillin with a cyclooxygenase-2 (COX-2) inhibitor (eg, celecoxib) was shown to be effective in improving antibiotic efficiency in vitro against several ampicillin-resistant Gram-negative bacterial pathogens, highlighting the utility of using small molecule adjuvants to improve antibiotic activity or overcoming antibiotic resistance 10. Thus, this approach provides a platform to screen untapped chemical space in combination with different antibiotics and thereby expands the scope of antibiotic discovery.…”

Section: Introductionmentioning

confidence: 99%

<p>Enhancing the antibacterial activity of polymyxins using a nonantibiotic drug</p>

Krishnamurthy¹,

Lemmon²,

Falcinelli³

et al. 2019

IDR

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Purpose: The rapid emergence of multidrug-resistant (MDR) bacteria and the lack of new therapies to eliminate them poses a major threat to global health. With the alarming rise in antimicrobial resistance (AMR), focus has now shifted to the use of the polymyxin class of antibiotics as the last line of defense for treatment of Gram-negative infections. Unfortunately, the growing resistance of bacteria against polymyxins is threatening the treatment of MDR infections, necessitating the need for novel strategies. The objective of this study was to determine if combination of polymyxin (polymyxin B or colistin) with a nonantibiotic small molecule AR-12, a celecoxib derivative that is devoid of cyclooxygenase 2 (COX-2) inhibitory activities, can be an effective strategy against polymyxin-resistant MDR bacteria. Methods: Growth inhibition studies, time-kill assays and permeability assays were conducted to investigate the effect of AR-12 on the antibacterial activity of polymyxins. Results: Growth studies were performed on a panel of polymyxin-resistant MDR strains using the combination of AR-12 with either colistin or polymyxin B. The combination treatment had no effect on strains that have inherent polymyxin resistance; however, AR-12 was effective in lowering the minimal inhibitory concentration (MIC) of polymyxins by 4–60-fold in several strains that had acquired polymyxin resistance. Time-kill assays using the combination of AR-12 and colistin with select MDR strains suggest rapid killing and bactericidal activity, while the permeability assays using fluorescently labeled dansylated polymyxin and 1-N-phenylnaphthylamine (NPN) in these MDR strains suggest that AR-12 can potentiate the antibacterial activity of polymyxins by possibly altering the bacterial outer membrane via modification of lipopolysaccharide and thereby improving the uptake of polymyxins. Conclusion: Our studies indicate that the combination of AR-12 and polymyxin is effective in targeting select Gram-negative bacteria that have acquired polymyxin resistance. Further understanding of the mechanism of action of AR-12 will provide new avenues for developing narrow-spectrum antibacterials to target select Gram-negative MDR bacteria. Importantly, our studies show that the use of nonantibiotic small molecules in combination with polymyxins is an attractive strategy to counter the growing resistance of bacteria to polymyxins.

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“…demonstrated the inhibitory effect of ginsenoside Rh1 on HMGB1-mediated sepsis response ( 25 ). In addition, celecoxib combined with low-dose antibiotics in treating sepsis in mice can significantly reduce the bacterial load and inflammatory markers in different organs of mice ( 26 ).…”

Section: Resultsmentioning

confidence: 99%

Diagnostic and predictive values of pyroptosis-related genes in sepsis

et al. 2023

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BackgroundSepsis is an organ dysfunction syndrome caused by the body’s dysregulated response to infection. Yet, due to the heterogeneity of this disease process, the diagnosis and definition of sepsis is a critical issue in clinical work. Existing methods for early diagnosis of sepsis have low specificity.AimsThis study evaluated the diagnostic and predictive values of pyroptosis-related genes in normal and sepsis patients and their role in the immune microenvironment using multiple bioinformatics analyses and machine-learning methods.MethodsPediatric sepsis microarray datasets were screened from the GEO database and the differentially expressed genes (DEGs) associated with pyroptosis were analyzed. DEGs were then subjected to multiple bioinformatics analyses. The differential immune landscape between sepsis and healthy controls was explored by screening diagnostic genes using various machine-learning models. Also, the diagnostic value of these diagnosis-related genes in sepsis (miRNAs that have regulatory relationships with genes and related drugs that have regulatory relationships) were analyzed in the internal test set and external test.ResultsEight genes (CLEC5A, MALT1, NAIP, NLRC4, SERPINB1, SIRT1, STAT3, and TLR2) related to sepsis diagnosis were screened by multiple machine learning algorithms. The CIBERSORT algorithm confirmed that these genes were significantly correlated with the infiltration abundance of some immune cells and immune checkpoint sites (all P<0.05). SIRT1, STAT3, and TLR2 were identified by the DGIdb database as potentially regulated by multiple drugs. Finally, 7 genes were verified to have significantly different expressions between the sepsis group and the control group (P<0.05).ConclusionThe pyroptosis-related genes identified and verified in this study may provide a useful reference for the prediction and assessment of sepsis.

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Celecoxib Enhances the Efficacy of Low-Dose Antibiotic Treatment against Polymicrobial Sepsis in Mice and Clinical Isolates of ESKAPE Pathogens

Cited by 16 publications

References 53 publications

As a Modulator, Multitasking Roles of SIRT1 in Respiratory Diseases

As a Modulator, Multitasking Roles of SIRT1 in Respiratory Diseases

<p>Enhancing the antibacterial activity of polymyxins using a nonantibiotic drug</p>

Diagnostic and predictive values of pyroptosis-related genes in sepsis

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