Modulation of Gingival Fibroblast Minocycline Accumulation by Biological Mediators

Walters, John D.; Nakkula, Robin J.; Maney, Pooja

doi:10.1177/154405910508400405

Cited by 8 publications

(8 citation statements)

References 23 publications

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“…This enhancement by TNF could potentially contribute to enhanced NSAID accumulation by fibroblasts in inflamed gingiva. A similar pattern of enhancement by TNF-αhas been reported with respect to minocycline transport by gingival fibroblasts (Walters et al, 2005).…”

Section: Discussionsupporting

confidence: 82%

Accumulation of Non-steroidal Anti-inflammatory Drugs by Gingival Fibroblasts

2006

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Non-steroidal anti-inflammatory drugs (NSAIDs) are used to manage pain and inflammatory disorders. We hypothesized that gingival fibroblasts actively accumulate NSAIDs and enhance their levels in gingival connective tissue. Using fluorescence to monitor NSAID transport, we demonstrated that cultured gingival fibroblasts transport naproxen in a saturable, temperaturedependent manner with a K m of 127 μg/mL and aV max of 1.42 ng/min/μg protein. At steady state, the intracellular/extracellular concentration ratio was 1.9 for naproxen and 7.2 for ibuprofen. Naproxen transport was most efficient at neutral pH and was significantly enhanced upon cell treatment with TNF-α. In humans, systemically administered naproxen attained steady-state levels of 61.9 μg/mL in blood and 9.4 μg/g in healthy gingival connective tissue, while ibuprofen attained levels of 2.3 μg/mL and 1.5 μg/g, respectively. Thus, gingival fibroblasts possess transporters for NSAIDs that are up-regulated by an inflammatory mediator, but there is no evidence that they contribute to elevated NSAID levels in healthy gingiva.

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Section: Discussionsupporting

confidence: 82%

Accumulation of Non-steroidal Anti-inflammatory Drugs by Gingival Fibroblasts

2006

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“…5). Previous studies have shown that human gingival fibroblasts display an active transport mechanism for minocycline uptake (3,14). In cultured ARVF (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Minocycline transport in cardiac cells was measured fluorometrically in each seeded well as described (3,14) with modifications. Briefly, culture plates containing cell monolayers were washed 4× with Hank's Balance Salt Solution (HBSS), overlaid with HBSS and warmed to 37°C prior to assay.…”

Section: Methodsmentioning

confidence: 99%

Cardiac Uptake of Minocycline and Mechanisms for In Vivo Cardioprotection

Romero-Perez

Fricovsky

Yamasaki

et al. 2008

Journal of the American College of Cardiology

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Objectives The ability of minocycline to be transported into cardiac cells, concentrate in normal and ischemic myocardium and act as in vivo cardioprotector was examined. We also determined minocycline's capacity to act as a reducer of myocardial oxidative stress and matrix metalloproteinase (MMP) activity. Background The identification of compounds with the potential to reduce myocardial ischemic injury is of great interest. Tetracyclines (TTCs) are antibiotics with pleiotropic cytoprotective properties that accumulate in normal and diseased tissues. Minocycline is highly lipophilic and has shown promise as a possible cardioprotector. However, minocycline's potential as an in vivo cardioprotector as well as the means by which this action is attained are not well understood. Methods Rats were subjected to 45 min of ischemia and 48 h of reperfusion. Animals were treated 48 h before and 48 h after thoracotomy with either vehicle or 50 mg/kg/day minocycline. Tissue samples were used for biochemical assays and cultured cardiac cells for minocycline uptake experiments. Results Minocycline significantly reduced infarct size (∼33%), tissue MMP-9 activity and oxidative stress. Minocycline was concentrated ∼24-fold in normal (0.5 mM) and ∼50-fold in ischemic regions (1.1 mM) vs. blood. Neonatal rat cardiac fibroblasts, myocytes and adult fibroblasts demonstrate a time- and temperature-dependent uptake of minocycline to levels that approximate those of normal myocardium. Conclusions Given the high intracellular levels observed and results from the assessment of in vitro antioxidant and MMP inhibitor capacities, it is likely that minocycline acts to limit myocardial ischemic injury via mass action effects.

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“…In terms of antimicrobial efficacy, tetracyclines have different affinities for the 30S bacterial ribosomal subunits resulting in different therapeutic efficacies [27]. Little information is available on the uptake and release of tetracyclines by mammalian cells [28,29] and no data are available for uptake by J774 cells. This is the first report to show that the new tetracycline compound tigecycline is able to inhibit LPS-induced nitric oxide production and release from macrophages.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of the anti‐inflammatory action of minocycline

Dunston¹,

Griffiths²,

Lambert³

et al. 2011

Proteomics Clinical Apps

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Minocycline possesses anti-inflammatory properties independently of its antibiotic activity although the underlying molecular mechanisms are unclear. Lipopolysaccharide (LPS)-induced cytokines and pro-inflammatory protein expression are reduced by minocycline in cultured macrophages. Here, we tested a range of clinically important tetracycline compounds (oxytetracycline, doxycycline, minocycline and tigecycline) and showed that they all inhibited LPS-induced nitric oxide production. We made the novel finding that tigecycline inhibited LPS-induced nitric oxide production to a greater extent than the other tetracycline compounds tested. To identify potential targets for minocycline, we assessed alterations in the macrophage proteome induced by LPS in the presence or absence of a minocycline pretreatment using 2-DE and nanoLC-MS. We found a number of proteins, mainly involved in cellular metabolism (ATP synthase b-subunit and aldose reductase) or stress response (heat shock proteins), which were altered in expression in response to LPS, some of which were restored, at least in part, by minocycline. This is the first study to document proteomic changes induced by minocycline. The observation that minocycline inhibits some, but not all, of the LPS-induced proteomic changes shows that minocycline specifically affects some signalling pathways and does not completely inhibit macrophage activation.

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Modulation of Gingival Fibroblast Minocycline Accumulation by Biological Mediators

Cited by 8 publications

References 23 publications

Accumulation of Non-steroidal Anti-inflammatory Drugs by Gingival Fibroblasts

Accumulation of Non-steroidal Anti-inflammatory Drugs by Gingival Fibroblasts

Cardiac Uptake of Minocycline and Mechanisms for In Vivo Cardioprotection

Proteomic analysis of the anti‐inflammatory action of minocycline

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