ABSTRACT
Rationale: One of the hallmarks of osteoarthritis (OA), the most common degenerative joint disease, is increased numbers of senescent chondrocytes. Targeting senescent chondrocytes or signaling mechanisms leading to senescence could be a promising new therapeutic approach for OA treatment. However, understanding the key targets and links between chondrocyte senescence and OA remains unclear. Methods: Senescent chondrocytes were identified from Nudt7-/-, Acot12-/-, double-knockout mice lacking Acot12 and Nudt7 (dKO) and applied to microarray. The presence of forkhead transcription factor M1 (FOXM1) was detected in aged, dKO, and destabilization of the medial meniscus (DMM) cartilages and articular chondrocytes, and the effect of FoxM1 overexpression and acetyl-CoA treatment on cartilage homeostasis was examined using immunohistochemistry, quantitative real-time PCR (qRT-PCR), cell apoptosis and proliferation assay, and safranin O staining. Delivery of Rho@PAA-MnO2 (MnO2 nanosheet) or heparin-ACBP/COS-GA-siFoxM1 (ACBP-siFoxM1) nanoparticles into DMM cartilage was performed. Results: Here, we propose the specific capture of acetyl-CoA with the delivery of (FoxM1 siRNA (siFoxM1) to prevent cartilage degradation by inhibiting the axis of chondrocyte senescence. dKO stimulate chondrocyte senescence via the upregulation of FoxM1 and contribute to severe cartilage breakdown. We found that the accumulation of acetyl-CoA in the dKO mice may be responsible for the upregulation of FoxM1 during OA pathogenesis. Moreover, scavenging reactive oxygen species (ROS) induced by chondrocyte senescence via the implantation of MnO2 nanosheets or delivery of siFoxM1 functionalized with acetyl-CoA binding protein (ACBP) to capture acetyl-CoA using an injectable bioactive nanoparticle (siFoxM1-ACBP-NP) significantly suppressed DMM-induced cartilage destruction. Conclusion: We found that the loss of Acot12 and Nudt7 stimulates chondrocyte senescence via the upregulation of FoxM1 and accumulation of acetyl-CoA, and the application of siFoxM1-ACBP-NP is a potential therapeutic strategy for OA treatment.
Subject(s)
Chondrocytes , Osteoarthritis , Animals , Mice , Acetyl Coenzyme A/metabolism , Cellular Senescence/physiology , Chondrocytes/metabolism , Manganese Compounds/pharmacology , Mice, Knockout , Osteoarthritis/metabolism , Oxides/pharmacology , Nudix HydrolasesABSTRACT
The aim of this study was to evaluate the effectiveness of cefepime compared with carbapenems for the management of urinary tract infections (UTIs) caused by extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae. This was a single-centre, retrospective study among patients with a documented ESBL-producing Enterobacteriaceae UTI between 1 July 2014 and 31 January 2017. Adult patients who received either cefepime or a carbapenem for symptomatic UTI were included in the analysis. The primary endpoint was clinical failure, defined by persistence of initial UTI symptoms that required escalation of therapy. Secondary endpoints included microbiological failure and relapse within 30 days. Of a total of 106 patients included in the study, 17 received cefepime and 89 received a carbapenem. None of the patients in either group experienced clinical or microbiological failure. Relapse occurred in six patients in the carbapenem group and none in the cefepime group. In conclusion, cefepime was comparable with carbapenems in the treatment of UTIs caused by ESBL-producing Enterobacteriaceae. Its use as a carbapenem-sparing agent for this indication should be further explored.
