Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells

Badal, Sujan; Her, Yeng F.; Maher, L. James

doi:10.1074/jbc.m115.671222

Cited by 84 publications

(63 citation statements)

References 75 publications

(88 reference statements)

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“…In relation to tendon biology, expression of G9a, a methyltransferase with specific affinity to the ninth lysine residue of histone three, was shown to regulate cellular differentiation in mouse tenocytes by expression of tenogenic transcription factors, including Scleraxis and Mohawk, which have been heavily studied as necessary modulators for proper tendon development . Additionally, the use of fluoroquinolones (linked to tendinopathy in human patients) in human embryonic kidney cell cultures resulted in the inhibition of DNA methylases, collagen prolyl 4‐hydroxylases, and hypoxia inducible factor 1a (also linked to tendinopathy), suggesting a mechanistic epigenetic link to chronic tendinopathy …”

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confidence: 99%

“…19 Additionally, the use of fluoroquinolones (linked to tendinopathy in human patients 20 ) in human embryonic kidney cell cultures resulted in the inhibition of DNA methylases, collagen prolyl 4-hydroxylases, and hypoxia inducible factor 1a (also linked to tendinopathy 21 ), suggesting a mechanistic epigenetic link to chronic tendinopathy. 22 While these recent studies suggest the important role of epigenetics in tendon biology, to our knowledge there are no published studies on analyses for altered DNA methylation and histone modification in human tendinopathies or animal models of the disease. The current study was carried out, using a murine model of Achilles tendinopathy, to identify changes in expression of epigenetic modification enzymes, and to subsequently perform a genomewide screening for changes in methylation of gene promoter regions associated with the development of the disease.…”

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confidence: 99%

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Genome-wide analysis identifies differential promoter methylation of Leprel2 , Foxf1 , Mmp25, Igfbp6 , and Peg12 in murine tendinopathy

Trella

Stylianou

et al. 2016

J. Orthop. Res.

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We have used a murine Achilles tendinopathy model to investigate whether tissue changes (such as collagen disorganization, chondroid metaplasia, and loss of tensile properties) which are broadly characteristic of human tendinopathies, are accompanied by changes in the expression of chromatin-modifying enzymes and the methylation status of promoter regions of tendon cell DNA. Tendinopathy was induced by two intra-tendinous TGF-β1 injections followed by cage activity or treadmill running for up to 28 days. Activation of DNA methyltransferases occurred at 3 days after the TGF-β1 injections and also at 14 days, but only with treadmill activity. Genome wide Methyl Mini-Seq™ analysis identified 19 genes with differentially methylated promoters, five of which perform functions with an apparent direct relevance to tendinopathy (Leprel2, Foxf1, Mmp25, Igfbp6 and Peg12). The functions of the genes identified included collagen fiber assembly and pericellular interactions, therefore their perturbation could play a role in the characteristic disorganization of fibers in affected tendons. We postulate that a study of the functional genomics of these genes in animal and human tendon could further delineate the pathogenesis of this multi-factorial complex disease.

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confidence: 99%

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confidence: 99%

Genome-wide analysis identifies differential promoter methylation of Leprel2 , Foxf1 , Mmp25, Igfbp6 , and Peg12 in murine tendinopathy

Trella

Stylianou

et al. 2016

J. Orthop. Res.

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“…But the potential for mitochondrial damage still isn't widely appreciated 8 , reported that fluoroquinolones can bind to iron atoms from the active sites of several enzymes that modify DNA, leading to epigenetic changes that might be related to some of the drugs' side effects.…”

Section: Mitochondrial Damagementioning

confidence: 99%

When antibiotics turn toxic

Marchant

2018

Nature

127

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“…Antibiotics can have a variety of microbiota-independent effects on mammalian cells. Antibiotics can illicit profound changes in host gene expression in both conventional and germ-free mice (11), alter mammalian metabolic pathways and impair the phagocytic activity of immune cells (12), induce mitochondrial dysfunction (13, 14), and inhibit histone demethylases (15). Additionally, Gopinath et al recently demonstrated that aminoglycoside antibiotics can confer microbiota-independent antiviral resistance against both DNA and RNA viruses by upregulating expression of interferon-stimulated genes (16).…”

Section: Introductionmentioning

confidence: 99%

The Antibiotic Neomycin Enhances Coxsackievirus Plaque Formation

Acevedo

Pfeiffer

2018

Preprint

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word count: 15 Text word count: 16 Abstract 24Coxsackievirus typically infects humans via the gastrointestinal tract, which has a 25 large number of microorganisms collectively referred to as the microbiota. To study how 26 the intestinal microbiota influence enteric virus infection, several groups have used an 27 antibiotic regimen in mice to deplete bacteria. These studies have shown that bacteria 28 promote infection with several enteric viruses. However, very little is known about 29 whether antibiotics influence viruses in a microbiota-independent manner. Here, we 30 sought to determine the effects of antibiotics on coxsackievirus B3 (CVB3) using an in 31 vitro cell culture model in the absence of bacteria. We determined that an 32 aminoglycoside antibiotic, neomycin, enhanced plaque size of CVB3-Nancy strain. 33 Neomycin treatment did not alter viral attachment, translation, or replication. However, 34 we found that the positive charge of neomycin and other positively charged compounds 35 enhanced viral diffusion by overcoming the negative inhibitory effect of sulfated 36 polysaccharides present in agar overlays. Overall, these data lend further evidence that 37 antibiotics can play non-canonical roles in viral infections and that this should be 38 considered when studying enteric virus-microbiota interactions. 39 40 Importance 41 Coxsackieviruses primarily infect the gastrointestinal tract of humans, but they 42 can disseminate systemically and cause severe disease. Using antibiotic treatment 43 regimens to deplete intestinal microbes in mice, several groups have shown the 44 bacteria promote infection with a variety of enteric viruses. However, it is possible that 45 antibiotics have microbiota-independent effects on viruses. Here, we show that 46 an aminoglycoside antibiotic, neomycin, can influence quantification of coxsackievirus 47 in cultured cells in absence of bacteria.48 49 Introduction 50 Coxsackievirus B3 (CVB3) is a cardiotropic nonenveloped RNA virus belonging 51 to the Enterovirus genus of the Picornaviridae family. CVB3 is an important human 52 pathogen, which can cause a wide range of diseases, including myocarditis, cardiac 53 arrhythmias, aseptic meningitis, type 1 diabetes, gastrointestinal distress, and death (1-54 5). CVB3 has been implicated in over 40,000 infections a year in the United States 55alone and there are no current treatments or vaccines for CVB3 infections (6). 56Within the gastrointestinal tract resides a microbial ecosystem of approximately 57 10 14 organisms, which play a crucial role in host homeostasis (7). The intestinal 58 microbiota can also influence infection with orally acquired enteric viruses (8-10). 59Alterations in microbiota, for example through antibiotic treatment, can influence enteric 60 pathogen susceptibility (8-10). However, not much is known about direct effects of 61 antibiotics on enteric viruses. 62Antibiotics can have a variety of microbiota-independent effects on mammalian 63 cells. Antibiotics can illicit profound changes in host gene e...

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Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells

Cited by 84 publications

References 75 publications

Genome-wide analysis identifies differential promoter methylation of Leprel2 , Foxf1 , Mmp25, Igfbp6 , and Peg12 in murine tendinopathy

Genome-wide analysis identifies differential promoter methylation of Leprel2 , Foxf1 , Mmp25, Igfbp6 , and Peg12 in murine tendinopathy

When antibiotics turn toxic

The Antibiotic Neomycin Enhances Coxsackievirus Plaque Formation

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