Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we describe a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we describe a COA3Y72C mouse, affected in an assembly factor that cooperates with COX14 in early COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides insight into a link between defective mitochondrial gene expression and tissue-specific inflammation.

• MeSH
• Cyclooxygenase 1 * MeSH
• DEAD Box Protein 58 MeSH
• DEAD-box RNA Helicases metabolism   genetics   MeSH
• Liver * metabolism   pathology   MeSH
• Humans MeSH
• Membrane Proteins MeSH
• Mitochondrial Proteins metabolism   genetics   MeSH
• Mitochondria metabolism   MeSH
• Mutation MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Oxidative Phosphorylation * MeSH
• Protein Biosynthesis MeSH
• Reactive Oxygen Species * metabolism   MeSH
• Electron Transport Complex IV * metabolism   genetics   MeSH
• RNA, Mitochondrial genetics   metabolism   MeSH
• Inflammation * metabolism   genetics   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Bordetella pertussis infects the upper airways of humans and disarms host defense by the potent immuno-subversive activities of its pertussis (PT) and adenylate cyclase (CyaA) toxins. CyaA action near-instantly ablates the bactericidal activities of sentinel CR3-expressing myeloid phagocytes by hijacking cellular signaling pathways through the unregulated production of cAMP. Moreover, CyaA-elicited cAMP signaling also inhibits the macrophage colony-stimulating factor (M-CSF)-induced differentiation of incoming inflammatory monocytes into bactericidal macrophages. We show that CyaA/cAMP signaling via protein kinase A (PKA) downregulates the M-CSF-elicited expression of monocyte receptors for transferrin (CD71) and hemoglobin-haptoglobin (CD163), as well as the expression of heme oxygenase-1 (HO-1) involved in iron liberation from internalized heme. The impact of CyaA action on CD71 and CD163 levels in differentiating monocytes is largely alleviated by the histone deacetylase inhibitor trichostatin A (TSA), indicating that CyaA/cAMP signaling triggers epigenetic silencing of genes for micronutrient acquisition receptors. These results suggest a new mechanism by which B. pertussis evades host sentinel phagocytes to achieve proliferation on airway mucosa.IMPORTANCETo establish a productive infection of the nasopharyngeal mucosa and proliferate to sufficiently high numbers that trigger rhinitis and aerosol-mediated transmission, the pertussis agent Bordetella pertussis deploys several immunosuppressive protein toxins that compromise the sentinel functions of mucosa patrolling phagocytes. We show that cAMP signaling elicited by very low concentrations (22 pM) of Bordetella adenylate cyclase toxin downregulates the iron acquisition systems of CD14+ monocytes. The resulting iron deprivation of iron, a key micronutrient, then represents an additional aspect of CyaA toxin action involved in the inhibition of differentiation of monocytes into the enlarged bactericidal macrophage cells. This corroborates the newly discovered paradigm of host defense evasion mechanisms employed by bacterial pathogens, where manipulation of cellular cAMP levels blocks monocyte to macrophage transition and replenishment of exhausted phagocytes, thereby contributing to the formation of a safe niche for pathogen proliferation and dissemination.

• MeSH
• Adenylate Cyclase Toxin * metabolism   genetics   MeSH
• Cyclic AMP * metabolism   MeSH
• Antigens, Differentiation, Myelomonocytic MeSH
• Bordetella pertussis * MeSH
• Cell Differentiation * MeSH
• Antigens, CD metabolism   genetics   MeSH
• Humans MeSH
• Lipopolysaccharide Receptors * metabolism   MeSH
• Monocytes * metabolism   immunology   microbiology   MeSH
• Cyclic AMP-Dependent Protein Kinases metabolism   MeSH
• Receptors, Cell Surface metabolism   genetics   MeSH
• Signal Transduction * MeSH
• Up-Regulation MeSH
• Iron metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

We analyzed gene expression in THP-1 cells exposed to metal-based nanomaterials (NMs) [TiO2 (NM-100), ZnO (NM-110), SiO2 (NM-200), Ag (NM-300 K)]. A functional enrichment analysis of the significant differentially expressed genes (DEGs) identified the key modulated biological processes and pathways. DEGs were used to construct protein-protein interaction networks. NM-110 and NM-300 K induced changes in the expression of genes involved in oxidative and genotoxic stress, immune response, alterations of cell cycle, detoxification of metal ions and regulation of redox-sensitive pathways. Both NMs shared a number of highly connected protein nodes (hubs) including CXCL8, ATF3, HMOX1, and IL1B. NM-200 induced limited transcriptional changes, mostly related to the immune response; however, several hubs (CXCL8, ATF3) were identical with NM-110 and NM-300 K. No effects of NM-100 were observed. Overall, soluble nanomaterials NM-110 and NM-300 K exerted a wide variety of toxic effects, while insoluble NM-200 induced immunotoxicity; NM-100 caused no detectable changes on the gene expression level.

• MeSH
• Heme Oxygenase-1 MeSH
• Interleukin-8 metabolism   genetics   MeSH
• Metal Nanoparticles toxicity   MeSH
• Humans MeSH
• Protein Interaction Maps * drug effects   MeSH
• Nanostructures toxicity   MeSH
• Silicon Dioxide toxicity   MeSH
• Zinc Oxide toxicity   chemistry   MeSH
• Silver * toxicity   MeSH
• THP-1 Cells MeSH
• Titanium * toxicity   MeSH
• Activating Transcription Factor 3 genetics   metabolism   MeSH
• Transcriptome drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: The aim of this study was to: (1) evaluate the anti-inflammatory effects of cannabidiol (CBD) on primary cultures of human gingival fibroblasts (HGFs) and (2) to clinically monitor the effect of CBD in subjects with periodontitis. BACKGROUND: The use of phytocannabinoids is a new approach in the treatment of widely prevalent periodontal disease. MATERIALS AND METHODS: Cannabinoid receptors were analyzed by western blot and interleukin production detected using enzyme immunoassay. Activation of the Nrf2 pathway was studied via monitoring the mRNA level of heme oxygenase-1. Antimicrobial effects were determined by standard microdilution and 16S rRNA screening. In the clinical part, a placebo-control double-blind randomized study was conducted (56 days) in three groups (n = 90) using dental gel without CBD (group A) and with 1% (w/w) CBD (group B) and corresponding toothpaste (group A - no CBD, group B - with CBD) for home use to maintain oral health. Group C used dental gel containing 1% chlorhexidine digluconate (active comparator) and toothpaste without CBD. RESULTS: Human gingival fibroblasts were confirmed to express the cannabinoid receptor CB2. Lipopolysaccharide-induced cells exhibited increased production of pro-inflammatory IL-6 and IL-8, with deceasing levels upon exposure to CBD. CBD also exhibited antimicrobial activities against Porphyromonas gingivalis, with an MIC of 1.5 μg/mL. Activation of the Nrf2 pathway was also demonstrated. In the clinical part, statistically significant improvement was found for the gingival, gingival bleeding, and modified gingival indices between placebo group A and CBD group B after 56 days. CONCLUSIONS: Cannabidiol reduced inflammation and the growth of selected periodontal pathogenic bacteria. The clinical trial demonstrated a statistically significant improvement after CBD application. No adverse effects of CBD were reported by patients or observed upon clinical examination during the study. The results are a promising basis for a more comprehensive investigation of the application of non-psychotropic cannabinoids in dentistry.

• MeSH
• Anti-Inflammatory Agents therapeutic use   pharmacology   MeSH
• Chlorhexidine therapeutic use   pharmacology   analogs & derivatives   MeSH
• Adult MeSH
• Double-Blind Method MeSH
• NF-E2-Related Factor 2 MeSH
• Fibroblasts * drug effects   MeSH
• Gingiva * drug effects   MeSH
• Gingivitis * drug therapy   MeSH
• Heme Oxygenase-1 MeSH
• Interleukin-6 analysis   MeSH
• Interleukin-8 drug effects   MeSH
• Cannabidiol * pharmacology   therapeutic use   MeSH
• Cells, Cultured MeSH
• Middle Aged MeSH
• Humans MeSH
• Periodontitis drug therapy   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH

Oxidative stress and autophagy are potential mechanisms associated with cerebral ischemia/reperfusion injury (IRI) and is usually linked to inflammatory responses and apoptosis. Curcumin has recently been demonstrated to exhibit anti-inflammatory, anti-oxidant, anti-apoptotic and autophagy regulation properties. However, mechanism of curcumin on IRI-induced oxidative stress and autophagy remains not well understood. We evaluated the protective effects and potential mechanisms of curcumin on cerebral microvascular endothelial cells (bEnd.3) and neuronal cells (HT22) against oxygen glucose deprivation/reoxygenation (OGD/R) in vitro models that mimic in vivo cerebral IRI. The cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) activity assays revealed that curcumin attenuated the OGD/R-induced injury in a dose-specific manner. OGD/R induced elevated levels of inflammatory cytokines TNF-alpha, IL-6 as well as IL-1beta, and these effects were notably reduced by curcumin. OGD/R-mediated apoptosis was suppressed by curcumin via upregulating B-cell lymphoma-2 (Bcl-2) and downregulating Bcl-associated X (Bax), cleaved-caspase3 and TUNEL apoptosis marker. Additionally, curcumin increased superoxide dismutase (SOD) and glutathione (GSH), but suppressed malondialdehyde (MDA) and reactive oxygen species (ROS) content. Curcumin inhibited the levels of autophagic biomarkers such as LC3 II/LC3 I and Beclin1. Particularly, curcumin induced p62 accumulation and its interactions with keap1 and promoted NF-E2-related factor 2 (Nrf2) translocation to nucleus, accompanied by increased NADPH quinone dehydrogenase (Nqo1) and heme oxygenase 1 (HO-1). Treatment of curcumin increased phosphorylation-phosphatidylinositol 3 kinase (p-PI3K) and p-protein kinase B (p-AKT). The autophagy inhibitor 3-methyladenine (3-MA) activated the keap-1/Nrf2 and PI3K/AKT pathways. This study highlights the neuroprotective effects of curcumin on cerebral IRI.

• MeSH
• Antioxidants pharmacology   metabolism   MeSH
• Autophagy physiology   MeSH
• Endothelial Cells metabolism   MeSH
• NF-E2-Related Factor 2 metabolism   MeSH
• Phosphatidylinositol 3-Kinases metabolism   MeSH
• Kelch-Like ECH-Associated Protein 1 metabolism   MeSH
• Curcumin * pharmacology   MeSH
• Oxygen metabolism   MeSH
• Neuroprotective Agents * pharmacology   MeSH
• Oxidative Stress MeSH
• Proto-Oncogene Proteins c-akt metabolism   MeSH
• Signal Transduction MeSH
• Publication type
• Journal Article MeSH

Bilirubin has potent biological beneficial effects, protecting against atherosclerosis, obesity, and metabolic syndrome. The aim of this study was to assess serum bilirubin concentrations and (TA)n and (GT)n microsatellite variations in the promoter regions of the UGT1A1 and HMOX1 genes, respectively, in patients with type 2 diabetes mellitus (T2DM). The study was carried out in 220 patients with T2DM and 231 healthy control subjects, in whom standard biochemical tests were performed. The (TA)n and (GT)n dinucleotide variations were determined by means of fragment (size-based) analysis using an automated capillary DNA sequencer. Compared to controls, both male and female patients with T2DM had lower serum bilirubin concentrations (9.9 vs. 12.9 μmol/L, and 9.0 vs. 10.6 μmol/L, in men and women, respectively, p < 0.001). Phenotypic Gilbert syndrome was much less prevalent in T2DM patients, as was the frequency of the (TA)7/7UGT1A1 genotype in male T2DM patients. (GT)nHMOX1 genetic variations did not differ between diabetic patients and controls. Our results demonstrate that the manifestation of T2DM is associated with lower serum bilirubin concentrations. Consumption of bilirubin due to increased oxidative stress associated with T2DM seems to be the main explanation, although (TA)n repeat variations in UGT1A1 partially contribute to this phenomenon.

• MeSH
• Bilirubin metabolism   MeSH
• Diabetes Mellitus, Type 2 * genetics   MeSH
• Genotype MeSH
• Glucuronosyltransferase genetics   metabolism   MeSH
• Heme Oxygenase-1 genetics   metabolism   MeSH
• Humans MeSH
• Polymorphism, Genetic * MeSH
• Promoter Regions, Genetic MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

Bilirubin has several physiological functions, both beneficial and harmful. In addition to reactive oxygen species-scavenging activities, bilirubin has potent immunosuppressive effects associated with long-term pathophysiological sequelae. It has been recently recognized as a hormone with endocrine actions and interconnected effects on various cellular signaling pathways. Current studies show that bilirubin also decreases adiposity and prevents metabolic and cardiovascular diseases. All in all, the physiological importance of bilirubin is only now coming to light, and strategies for increasing plasma bilirubin levels to combat chronic diseases are starting to be considered. This review discusses the beneficial effects of increasing plasma bilirubin, incorporates emerging areas of bilirubin biology, and provides key concepts to advance the field.

• MeSH
• Bilirubin * metabolism   pharmacology   MeSH
• Heme Oxygenase-1 metabolism   MeSH
• Cardiovascular Diseases * MeSH
• Humans MeSH
• Reactive Oxygen Species metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH

The ultraviolet (UV) part of solar radiation can permanently affect skin tissue. UVA photons represent the most abundant UV component and stimulate the formation of intracellular reactive oxygen species (ROS), leading to oxidative damage to various biomolecules. Several plant-derived polyphenols are known as effective photoprotective agents. This study evaluated the potential of quercetin (QE) and its structurally related flavonoid taxifolin (TA) to reduce UVA-caused damage to human primary dermal fibroblasts (NHDF) and epidermal keratinocytes (NHEK) obtained from identical donors. Cells pre-treated with QE or TA (1 h) were then exposed to UVA light using a solar simulator. Both flavonoids effectively prevented oxidative damage, such as ROS generation, glutathione depletion, single-strand breaks formation and caspase-3 activation in NHDF. These protective effects were accompanied by stimulation of Nrf2 nuclear translocation, found in non-irradiated and irradiated NHDF and NHEK, and expression of antioxidant proteins, such as heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1 and catalase. For most parameters, QE was more potent than TA. On the other hand, TA demonstrated protection within the whole concentration range, while QE lost its protective ability at the highest concentration tested (75 μM), suggesting its pro-oxidative potential. In summary, QE and TA demonstrated UVA-protective properties in NHEK and NHDF obtained from identical donors. However, due to the in vitro phototoxic potential of QE, published elsewhere and discussed herein, further studies are needed to evaluate QE safety in dermatological application for humans as well as to confirm our results on human skin ex vivo and in clinical trials.

• MeSH
• Fibroblasts MeSH
• Flavonoids * metabolism   MeSH
• Keratinocytes MeSH
• Skin metabolism   MeSH
• Humans MeSH
• Oxidative Stress MeSH
• Quercetin * analogs & derivatives   pharmacology   MeSH
• Ultraviolet Rays MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Phototherapy is a golden standard treatment of severe neonatal jaundice. However, this treatment modality might be associated with significant health issues including increased overall mortality, increased risk of certain cancers or type 1 diabetes mellitus, especially in very low weight birth neonates. Despite a widespread use of phototherapy in clinical neonatology, only little is known about bilirubin oxidation products generated during phototherapy, and almost no studies have been performed to systematically explore the whole process of bilirubin photooxidation. All these aspects may account for observed clinical side effects. Thus, these issues are the main aim of the current project which combines interdisciplinary approach between life and basic sciences.

Fototerapie je standardním léčebným postupem u zavážné novorozenecké žloutenky. Tato léčba však může být doprovázena závažnými zdravotními dopady, které zahrnují zvýšení celkové mortality, zvýšený výskyt některých nádorových onemocnění, diabetu mellitu 1. typu, obzvláště u novorozenců s velmi nízkou porodní hmotností. I přes široké používání fototerapie v klinické neonatologii je velmi málo známo o biologických účincích oxidačních produktů bilirubinu, které vznikají během fototerapie novorozenecké žloutenky, a zcela chybí studie, které by se systematicky zabývaly celým procesem fotooxidace bilirubinu. Všechny tyto aspekty přitom mohou vysvětlit pozorované nežádoucí účinky fototerapie. Cílem předkládaného projektu je tedy systematické studium procesu fotooxidace bilirubinu za použití interdisciplinárního přístupu, který kombinuje biologické a chemické vědní obory.

• MeSH
• Bilirubin chemistry   metabolism   adverse effects   radiation effects   MeSH
• Phototherapy adverse effects   MeSH
• Heme Oxygenase-1 MeSH
• Infant, Newborn MeSH
• Jaundice, Neonatal therapy   MeSH
• Carbon Monoxide MeSH
• Oxidation-Reduction radiation effects   MeSH
• Risk Factors MeSH
• Check Tag
• Infant, Newborn MeSH

• Conspectus
• Pediatrie
• NML Fields
• biochemie
• perinatologie a neonatologie
• NML Publication type
• závěrečné zprávy o řešení grantu AZV MZ ČR

Background The FiGARO FFR versus iFR in Assessment of Hemodynamic Lesion Significance and an Explanation of Their Discrepancies trial is a prospective registry searching for predictors of fractional flow reserve instantaneous wave free ratio FFR iFR discrepancy Methods and Results FFR iFR were analyzed using a Verrata wire and coronary flow reserve was analyzed using a Combomap machine b

• MeSH
• Fractional Flow Reserve, Myocardial * MeSH
• Hemodynamics MeSH
• Hemoglobins MeSH
• Heme Oxygenase-1 genetics   MeSH
• Coronary Angiography methods   MeSH
• Coronary Stenosis * MeSH
• Humans MeSH
• Renal Insufficiency * MeSH
• Nitric Oxide Synthase Type III MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH