Clinical studies demonstrated the efficacy of Coenzyme Q10 (CoQ10) as an adjuvant therapeutic in cardiovascular diseases, mitochondrial myopathies and neurodegenerative diseases. More recently, expression profiling revealed that Coenzyme Q10 (CoQ10) influences the expression of several hundred genes. To unravel the functional connections of these genes, we performed a text mining approach using the Genomatix BiblioSphere. We identified signalling pathways of G-protein coupled receptors, JAK/STAT, and Integrin which contain a number of CoQ10 sensitive genes. Further analysis suggested that IL5, thrombin, vitronectin, vitronectin receptor, and C-reactive protein are regulated by CoQ10 via the transcription factor NFkappaB1. To test this hypothesis, we studied the effect of CoQ10 on the NFkappaB1-dependent pro-inflammatory cytokine TNF-alpha. As a model, we utilized the murine macrophage cell lines RAW264.7 transfected with human apolipoprotein E3 (apoE3, control) or pro-inflammatory apoE4. In the presence of 2.5 microM or 75 microM CoQ10 the LPS-induced TNF-alpha response was significantly reduced to 73.3 +/- 2.8% and 74.7 +/- 8.9% in apoE3 or apoE4 cells, respectively. Therefore, the in silico analysis as well as the cell culture experiments suggested that CoQ10 exerts anti-inflammatory properties via NFkappaB1-dependent gene expression.

BackgroundBoth resveratrol and vitamin C (ascorbic acid) are frequently used in complementary and alternative medicine. However, little is known about the underlying mechanisms for potential health benefits of resveratrol and its interactions with ascorbic acid.MethodsThe antioxidant enzymes heme oxygenase-1 and paraoxonase-1 were analysed for their mRNA and protein levels in HUH7 liver cells treated with 10 and 25 μmol/l resveratrol in the absence and presence of 100 and 1000 μmol/l ascorbic acid. Additionally the transactivation of the transcription factor Nrf2 and paraoxonase-1 were determined by reporter gene assays.ResultsHere, we demonstrate that resveratrol induces the antioxidant enzymes heme oxygenase-1 and paraoxonase-1 in cultured hepatocytes. Heme oxygenase-1 induction by resveratrol was accompanied by an increase in Nrf2 transactivation. Resveratrol mediated Nrf2 transactivation as well as heme oxygenase-1 induction were partly antagonized by 1000 μmol/l ascorbic acid.ConclusionsUnlike heme oxygenase-1 (which is highly regulated by Nrf2) paraoxonase-1 (which exhibits fewer ARE/Nrf2 binding sites in its promoter) induction by resveratrol was not counteracted by ascorbic acid. Addition of resveratrol to the cell culture medium produced relatively low levels of hydrogen peroxide which may be a positive hormetic redox-signal for Nrf2 dependent gene expression thereby driving heme oxygenase-1 induction. However, high concentrations of ascorbic acid manifold increased hydrogen peroxide production in the cell culture medium which may be a stress signal thereby disrupting the Nrf2 signalling pathway.

Dietary vitamin E (VE) is known to regulate gene expression by altering mRNA concentrations. Recently, micro-RNA (miRNA) have been discovered as a means of posttranscriptional gene regulation. Since the effect of VE on miRNA regulation is unknown, we fed rats for 6 months diets deficient or sufficient in VE and determined hepatic concentrations of miRNA involved in processes previously associated with VE (lipid metabolism, miRNA-122a; cancer and inflammation, miRNA-125b). VE-deficiency resulted in reduced concentrations of miRNA-122a and miRNA-125b. The findings of the present study demonstrate that differences in dietary VE may affect hepatic miRNA concentrations in vivo.

Summary Ubiquinol-10 (QH2), the reduced form of Coenzyme Q10 (CoQ10) serves as a potent antioxidant of lipid membranes. Because many antioxidants reveal potent anti-inflammatory effects, the influence of QH2 on lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and chemokines were determined in the human monocytic cell line THP-1. Stimulation of cells with LPS resulted in a distinct release of Tumour necrosis factor-alpha (TNF-α), Macrophage inflammatory protein-1 alpha (MIP-1α), Regulated upon activation, normal T cell expressed and secreted (RANTES) and Monocyte chemotattractant protein-1 (MCP-1). The LPS-induced responses were significantly decreased by pre-incubation of cells with QH2 to 60.27 ± 9.3% (p = 0.0009), 48.13 ± 6.93% (p = 0.0007) and 74.36 ± 7.25% (p = 0.008) for TNF-α, MIP-1α and RANTES, respectively. In conclusion, our results indicate anti-inflammatory effects of the reduced form of CoQ10 on various proinflammatory cytokines and chemokines in vitro.

Our present study reveals significant decelerating effects on senescence processes in middle-aged SAMP1 mice supplemented for 6 or 14 months with the reduced form (Q(10)H(2), 500 mg/kg BW/day) of coenzyme Q(10) (CoQ(10)). To unravel molecular mechanisms of these CoQ(10) effects, a genome-wide transcript profiling in liver, heart, brain and kidney of SAMP1 mice supplemented with the reduced (Q(10)H(2)) or oxidized form of CoQ(10) (Q(10)) was performed. Liver seems to be the main target tissue of CoQ(10) intervention, followed by kidney, heart and brain. Stringent evaluation of the resulting data revealed that Q(10)H(2) has a stronger impact on gene expression than Q(10), primarily due to differences in the bioavailability. Indeed, Q(10)H(2) supplementation was more effective than Q(10) to increase levels of CoQ(10) in the liver of SAMP1 mice. To identify functional and regulatory connections of the "top 50" (p<0.05) Q(10)H(2)-sensitive transcripts in liver, text mining analysis was used. Hereby, we identified Q(10)H(2)-sensitive genes which are regulated by peroxisome proliferator-activated receptor-alpha and are primarily involved in cholesterol synthesis (e.g. HMGCS1, HMGCL and HMGCR), fat assimilation (FABP5), lipoprotein metabolism (PLTP) and inflammation (STAT-1). These data may explain, at least in part, the decelerating effects on degenerative processes observed in Q(10)H(2)-supplemented SAMP1 mice.

SummaryStudies in vitro and in mice indicate a role for Coenzyme Q 10

Studies in humans and cell culture as well as bioinformatics suggested that Coenzyme Q(10) (CoQ10) functions as an anti-inflammatory molecule. Here we studied the influence of CoQ10 (Kaneka Q10) on secretion of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) by using the human and murine monocytic cell lines THP-1 and RAW264.7 expressing human apolipoprotein E3 (apoE3) or pro-inflammatory apoE4. Incubation of cells with physiological (0.1-10 microM) and supra-physiological (> 10 to < 100 microM) concentrations of CoQ10 led to an intracellular accumulation of its reduced form without any cytotoxic effects. Stimulation of cell models with lipopolysaccharide (LPS) resulted in a substantially release of TNF-alpha. When THP-1 cells were pre-incubated with 10 microM CoQ10, the LPS-induced TNF-alpha release was significantly decreased to 72 +/- 32%. This effect is similar to those obtained by 10 microM N-Acetyl-Cysteine, a well known reference antioxidant. In RAW264.7-apoE3 and -apoE4 cells, significant reductions of LPS-induced TNF-alpha secretion to 73.3 +/- 2.8% and 74.7 +/- 8.9% were found with 2.5 microM and 75 microM CoQ10, respectively. In conclusion, CoQ10 has moderate anti-inflammatory effects in two monocytic cell lines which could be mediated by its antioxidant activity.

Coenzyme Q_{10} (CoQ_{10}) is an obligatory element in the mitochondrial electron transport system and functions as a potent antioxidant of lipid membranes. In-vivo and in-vitro studies indicate an involvement of CoQ_{10} in inflammatory pathways. Here we studied in the human monocytic cell-line THP-1 the influence of CoQ_{10} on LPS-induced secretion of the pro-inflammatory chemokines Macrophage inflammatory protein-1 alpha (MIP-1alpha), Regulated upon activation, normal T cell expressed and secreted (RANTES) and Monocyte chemoattractant protein-1 (MCP-1). In comparison to unstimulated cells, LPS leads to 22-, 3- and 4.5-fold higher levels of MIP-1alpha, RANTES and MCP-1 in the cell culture medium, respectively. Pre-incubation of cells with 10 microM CoQ_{10} resulted in a significant decrease of LPS-induced MIP-1alpha and RANTES secretion to 55.04% (p = 0.02) and 76.84% (p = 0.04), respectively. In conclusion, CoQ_{10} reduces the LPS-induced secretion levels of the pro-inflammatory chemokines MIP-1alpha and RANTES in the human monocytic cell line THP-1. These data suggest that CoQ_{10} possesses anti-inflammatory properties.