Vorinostat in the acute neuroinflammatory form of X-linked adrenoleukodystrophy.

OBJECTIVE: To identify a pharmacological compound targeting macrophages, the most affected immune cells in inflammatory X-linked adrenoleukodystrophy (cerebral X-ALD) caused by ABCD1 mutations and involved in the success of hematopoietic stem cell transplantation and gene therapy. METHODS: A comparative database analysis elucidated the epigenetic repressing mechanism of the related ABCD2 gene in macrophages and identified the histone deacetylase (HDAC) inhibitor Vorinostat as a compound to induce ABCD2 in these cells to compensate for ABCD1 deficiency. In these cells, we investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal ß-oxidation activity, accumulation of very long-chain fatty acids (VLCFAs) and their differentiation status. We investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal ß-oxidation activity, accumulation of very long-chain fatty acids (VLCFA) and differentiation status. Three advanced cerebral X-ALD patients received Vorinostat and CSF and MRI diagnostics was carried out in one patient after 80 days of treatment. RESULTS: Vorinostat improved the metabolic defects in X-ALD macrophages by stimulating ABCD2 expression, peroxisomal ß-oxidation, and ameliorating VLCFA accumulation. Vorinostat interfered with pro-inflammatory skewing of X-ALD macrophages by correcting IL12B expression and further reducing monocyte differentiation. Vorinostat normalized the albumin and immunoglobulin CSF-serum ratios, but not gadolinium enhancement upon 80 days of treatment. INTERPRETATION: The beneficial effects of HDAC inhibitors on macrophages in X-ALD and the improvement of the blood-CSF/blood-brain barrier are encouraging for future investigations. In contrast with Vorinostat, less toxic macrophage-specific HDAC inhibitors might improve also the clinical state of X-ALD patients with advanced inflammatory demyelination.

The effect of antimicrobial photodynamic therapy on the expression of biofilm associated genes in Staphylococcus aureus strains isolated from wound infections in burn patients.

PURPOSE: Burn patients are particularly susceptible to microbial infection. Staphylococcus aureus causes burn wound, impetigo and cellulitis. Although sub-lethal antimicrobial photodynamic therapy (aPDT) would not result in microorganism killing, it can considerably influence microbial virulence factor. METHODS: Twelve methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) isolated from burns patients. To determine the sub-lethal dose of aPDT, 12 clinical isolates of S. aureus photosensitized with 100 µg ml -1 toluidine blue O (TBO) and irradiated by light emitting diode (LED) with a wavelength of 630 ± 10 nm and energy densities of 52.0, 104.1, and 156.2 J/cm2, then bacterial viability was measured. The effects of sub-lethal aPDT on the expression levels of ica ABCD and ica R genes were assessed by quantitative Real-time PCR (qRT-PCR) method. RESULT: Fifty and 100 µg ml-1 of TBO significantly reduced the mean cell survival in the MRSA (2.5 - 3 log10) and MSSA (2.75-3.1 log10) isolates. The average expression levels of icaA, ica B, ica C, and ica D in the MRSA and MSSA isolates were decreased by (12, 14, 11, and 9) and (13, 14.5, 12, and 9.5) fold change, respectively (P < 0.05). However, the expression of ica R gene was decreased by 6 and 8 folds change in MRSA and MSSA, respectively. CONCLUSION: The potential of TBO-mediated aPDT could reduce the expression of ica ABCD as important genes involved in biofilm formation and ica R gene as a repressor of the ica operon. Therefore, the use of aPDT agents as a complementary therapy in wound infections of burn patients is recommended.