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.

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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 Q10 (CoQ10, ubiquinone) is an essential cofactor in the electron transport chain, serves as a potent antioxidant in mitochondria and lipid membranes, and is often used as a dietary supplement for a number of diseases including cardiovascular diseases. Recently, we obtained evidence that CoQ10 (Kaneka Q10™) affects the expression of hundreds of human genes. To decipher the functional and regulatory connections of these genes, a literature search combined with transcription factor binding site analysis was performed using Genomatix BiblioSphere and MatInspector. This in‐silico analysis revealed 17 CoQ10‐inducible genes which are functionally connected by signalling pathways of G‐protein coupled receptors, JAK/STAT, integrin, and beta‐arrestin. Promoter analysis of these CoQ10‐inducible genes showed one group of NFκ B‐regulated genes, namely IL5, thrombin, vitronectin receptor and C‐reactive protein (CRP). Furthermore, a common promoter framework containing binding sites of the transcription factor families EVI1, HOXF, HOXC, and CLOX was identified in the promoters of IL5, CRP, and vitronectin receptor. The identified CoQ10‐inducible genes and pathways play an important role in inflammatory response. Since these effects are based on an in‐vitro study, the effect of CoQ10 on vascular health in vivo needs to be addressed in further animal and/or human intervention studies. IUBMB Life, 59: 628‐633, 2007

To search for common variants etiological for type 2 diabetes, we screened 15 genes involved in fat assimilation for sequence variants. Approximately 55 kb in promoter and coding regions, and intron/splice sites were sequenced by cycle sequencing. In the set of 15 genes, 71 single nucleotide polymorphisms (SNPs) were detected. 33 SNPs were presumed to be functionally significant and were genotyped in 192 incident type 2 diabetes subjects and 384 matched controls from the European Prospective Investigation into Cancer and Nutrition-Potsdam cohort. A total of 27 SNPs out of 15 genes showed no statistical association with type 2 diabetes in our study. Six SNPs demonstrated nominal association with type 2 diabetes, with the most significant marker (FABP6 Thr79Met) having an adjusted odds ratio of 0.45 (95% CI 0.22-0.92) in homozygous Met allele carriers. Evidence for an association with disease status was also found for a novel Arg109Cys (g.2129C > T) variant of colipase, 5'UTR (rs2084202) and Met71Val (rs8192506) variants of diazepam-binding inhibitor, Arg298His (rs13283456) of PTGES2, and a novel promoter variant (g.-1324G > A) of SLC27A5. The results presented here provide preliminary evidence for the association of common variants in genes involved in fat assimilation with the genetic susceptibility of type 2 diabetes. However, they definitely need further verification.

The protein encoded by the pancreatic colipase (CLPS) gene is an essential cofactor needed by pancreatic triglyceride lipase (PNLIP) for efficient dietary lipid hydrolysis. Since the inhibition of lipase activity was shown to reduce the incidence of type 2 diabetes mellitus, we tested the hypothesis that genetic variations in the CLPS and PNLIP genes are associated with type 2 diabetes; 47 unrelated subjects were screened for polymorphisms of the CLPS and PNLIP genes. A nested-case control study of 192 incident type 2 diabetes subjects and 384 sex- and age-matched controls taken from the European Prospective Investigation into Cancer and Nutrition Potsdam Cohort (EPIC) was employed for association studies. The Metabolic Intervention Cohort Kiel (MICK) consisting of 716 males was used for verification. A novel putative functional polymorphism (Arg109Cys) was identified in the CLPS gene. The frequencies of the Arg/Cys genotype were 2.6% in EPIC and 2.2% in MICK study subjects. No homozygotes for the Cys/Cys genotype were found in either study population. Logistic regression analysis showed a statistically significant association of the Arg/Cys genotype with an increased risk of type 2 diabetes. The odds ratios estimated by the model were 3.75 (95%CI = 1.13-12.49, p = 0.03) in EPIC and 4.86 (95%CI = 1.13-20.95, p = 0.03) in MICK. No comparable associations were found with other traits of the insulin-resistance syndrome (e. g.; body mass index, waist to hip ratio). In conclusion, we obtained evidence in two German Caucasian study populations that the variant of the rare CLPS Arg109Cys polymorphism might contribute to increased susceptibility of type 2 diabetes.

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Dictyostelium discoideum plasmid Ddp2 from the wild strain WS380B is a 5.8-kilobase (kb) supercoiled circle with a copy number of 300 per haploid genome. We previously described the construction of an extrachromosomally replicating transformation vector pnDeI carrying 4.7 kb of Ddp2 sequences (B. Leiting, and A. Noegel, Plasmid 20:241-248, 1988). In order to reduce the sequences required for extrachromosomal maintenance in D. discoideum, we characterized Ddp2 by sequence analysis, by deletion experiments, by transcription mapping, by electrophoretic mobility shift assays, and by expression of its single open reading frame in Escherichia coli. Two elements were involved in replication of Ddp2: a cis-acting sequence located on a 592-base-pair (bp) fragment that consisted of 220 bp of essential and 372 bp of auxiliary sequences, and a 2.7-kb open reading frame which most likely encodes a trans-acting factor. The cis-and trans-acting elements did not overlap and were shown to act independently from the location of the sequences encoding the trans-acting factor.