TY - JOUR A1 - Schlagenhauf, Ulrich T1 - On the role of dietary nitrate in the maintenance of systemic and oral health JF - Dentistry Journal N2 - The assessment of the significance of nitrates ingested with food has undergone a fundamental change in recent years after many controversial discussions. While for a long time, a diet as low in nitrates as possible was advocated on the basis of epidemiological data suggesting a cancer-promoting effect of nitrate-rich diets, more recent findings show that dietary nitrate, after its conversion to nitrite by nitrate-reducing bacteria of the oral microbiota, is an indispensable alternative source for the formation of nitric oxide (NO), which comprises a key element in the physiology of a variety of central body functions such as blood pressure control, defense against invading bacteria and maintenance of a eubiotic microbiota in the gut and oral cavity. This compact narrative review aims to present the evidence supported by clinical and in vitro studies on the ambivalent nature of dietary nitrates for general and oral health and to explain how the targeted adjuvant use of nitrate-rich diets could open new opportunities for a more cause-related control of caries and periodontal disease. KW - nitric oxide KW - nitrite KW - nitrate KW - diet KW - oral KW - periodontitis KW - caries Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275168 SN - 2304-6767 VL - 10 IS - 5 ER - TY - JOUR A1 - Salvador, Ellaine A1 - Burek, Malgorzata A1 - Förster, Carola Y. T1 - Stretch and/or oxygen glucose deprivation (OGD) in an in vitro traumatic brain injury (TBI) model induces calcium alteration and inflammatory cascade JF - Frontiers in Cellular Neuroscience N2 - The blood-brain barrier (BBB), made up of endothelial cells of capillaries in the brain, maintains the microenvironment of the central nervous system. During ischemia and traumatic brain injury (TBI), cellular disruption leading to mechanical insult results to the BBB being compromised. Oxygen glucose deprivation (OGD) is the most commonly used in vitro model for ischemia. On the other hand, stretch injury is currently being used to model TBI in vitro. In this paper, the two methods are used alone or in combination, to assess their effects on cerebrovascular endothelial cells cEND in the presence or absence of astrocytic factors. Applying severe stretch and/or OGD to cEND cells in our experiments resulted to cell swelling and distortion. Damage to the cells induced release of lactate dehydrogenase enzyme (LDH) and nitric oxide (NO) into the cell culture medium. In addition, mRNA expression of inflammatory markers interleukin (I L)-6, IL-1\(\alpha\) chemokine (C-C motif) ligand 2 (CCL2) and tumor necrosis factor (TNF)-\(\alpha\) also increased. These events could lead to the opening of calcium ion channels resulting to excitotoxicity. This could be demonstrated by increased calcium level in OGD-subjected cEND cells incubated with astrocyte-conditioned medium. Furthermore, reduction of cell membrane integrity decreased tight junction proteins claudin-5 and occludin expression. In addition, permeability of the endothelial cell monolayer increased. Also, since cell damage requires an increased uptake of glucose, expression of glucose transporter glut1 was found to increase at the mRNA level after OGD. Overall, the effects of OGD on cEND cells appear to be more prominent than that of stretch with regards to TJ proteins, NO, glutl expression, and calcium level. Astrocytes potentiate these effects on calcium level in cEND cells. Combining both methods to model TBI in vitro shows a promising improvement to currently available models. KW - receptor antagonist KW - cytokine expression KW - tight junctions KW - cell stretch KW - calcium level KW - nitric oxide KW - endothelial cells KW - necrosis factor alpha KW - barrier properties KW - cerebral ischemia KW - nervous system KW - CNS injury KW - blood brain barrier KW - cEND KW - astrocytes KW - traumatic brain injury KW - oxygen-glucose deprivation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148255 VL - 9 IS - 323 ER - TY - JOUR A1 - Preising, Christina A1 - Schneider, Reinhard A1 - Bucher, Michael A1 - Gekle, Michael A1 - Sauvant, Christoph T1 - Regulation of expression of renal organic anion transporters OAT1 and OAT3 in a model of ischemia/reperfusion injury JF - Cellular Physiology and Biochemistry N2 - Background: Recently, we gained evidence that impairment of rOat1 and rOat3 expression induced by ischemic acute kidney injury (AKI) is mediated by COX metabolites and this suppression might be critically involved in renal damage. Methods: (i) Basolateral organic anion uptake into proximal tubular cells after model ischemia and reperfusion (I/R) was investigated by fluorescein uptake. The putative promoter sequences from hOAT1 (SLC22A6) and hOAT3 (SCL22A8) were cloned into a reporter plasmid, transfected into HEK cells and (ii) transcriptional activity was determined after model ischemia and reperfusion as a SEAP reporter gen assay. Inhibitors or antagonists were applied with the beginning of reperfusion. Results: By using inhibitors of PKA (H89) and PLC (U73122), antagonists of E prostanoid receptor type 2 (AH6809) and type 4 (L161,982), we gained evidence that I/R induced down regulation of organic anion transport is mediated by COX1 metabolites via E prostanoid receptor type 4. The latter signaling was confirmed by application of butaprost (EP2 agonist) or TCS2510 (EP4 agonist) to control cells. In brief, the latter signaling was verified for the transcriptional activity in the reporter gen assay established. Therein, selective inhibitors for COX1 (SC58125) and COX2 (SC560) were also applied. Conclusion: Our data show (a) that COX1 metabolites are involved in the regulation of renal organic anion transport(ers) after I/R via the EP4 receptor and (b) that this is due to transcriptional regulation of the respective transporters. As the promoter sequences cloned were of human origin and expressed in a human renal epithelial cell line we (c) hypothesize that the regulatory mechanisms described after I/R is meaningful for humans as well. KW - opossum kidney cells KW - prostaglandin e2 KW - reperfusion KW - transport experiments KW - translation KW - reporter gen assay KW - cloning of putative human promoter sequence KW - regulation of expression KW - OAT1 KW - OAT3 KW - OK cells KW - ischemic acute kidney injury model KW - HEK cells KW - ischemia KW - down regulation KW - nitric oxide KW - cellular physiology KW - cortical OAT1 KW - blood flow Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144504 VL - 37 IS - 1 ER - TY - JOUR A1 - Montoya Peláez, Guillermo L. A1 - Sierra, Jelver A. A1 - Alzate, Fernando A1 - Holzgrabe, Ulrike A1 - Ramirez-Pineda, José R. T1 - Pentacyclic triterpenes from Cecropia telenitida with immunomodulatory activity on dendritic cells JF - Revista Brasileira de Farmacognosia - Brazilian Journal of Pharmacognosy N2 - Pentacyclic triterpenes are a large family of plant metabolites that exhibit a wide array of biological activities. The genus Cecropia, which encompasses many plant species, has been used as traditional medicine for the treatment of inflammatory diseases and is known to produce many active pentacyclic triterpenes. In this study we investigated the chemical composition of a pentacyclic triterpene fraction from the roots of Cecropia telenitida Cuatrec., Urticaceae. A novel compound, which we termed yarumic acid, and four known molecules (serjanic acid, spergulagenic acid A, 20-hydroxy-ursolic acid and goreishic acid I) were isolated and characterised. In a dendritic cell (DC)-based assay, we demonstrated that non-toxic doses of these pentacyclic triterpenes inhibited the secretion of at least one of the proinflammatory cytokines tested (IL-1 beta, IL-12p40, IL-12p70, TNF-alpha). Spergulagenic acid A also inhibited nitric oxide production in lipopolysaccharide-stimulated dendritic cell. Serjanic acid and spergulagenic acid A, which were the most potent abundant compounds in the pentacyclic triterpene fraction, showed the most activity in the dendritic cell-based assay. These results show that all pentacyclic triterpenes might contribute to the anti-inflammatory activities of C. telenitida. Moreover, yarumic acid as well as the four known pentacyclic triterpenes, can be exploited as potential immunomodulatory/anti-inflammatory agents. KW - psidium guajava; KW - oleanane saponins KW - kappa-B activation KW - cytokine production KW - chenopodium quinoa KW - obtusifolia bertol KW - nitric oxide KW - ursolic acid KW - bone marrow KW - macrophages KW - pentacyclic triterpene KW - dendritic cells KW - anti-inflammatory activity KW - cytokine modulation KW - natural product KW - cecropia telenitida Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131851 VL - 23 ER - TY - JOUR A1 - Korkmaz, Yüksel A1 - Puladi, Behrus A1 - Galler, Kerstin A1 - Kämmerer, Peer W. A1 - Schröder, Agnes A1 - Gölz, Lina A1 - Sparwasser, Tim A1 - Bloch, Wilhelm A1 - Friebe, Andreas A1 - Deschner, James T1 - Inflammation in the human periodontium induces downregulation of the α\(_1\)- and β\(_1\)-subunits of the sGC in cementoclasts JF - International Journal of Molecular Sciences N2 - Nitric oxide (NO) binds to soluble guanylyl cyclase (sGC), activates it in a reduced oxidized heme iron state, and generates cyclic Guanosine Monophosphate (cGMP), which results in vasodilatation and inhibition of osteoclast activity. In inflammation, sGC is oxidized and becomes insensitive to NO. NO- and heme-independent activation of sGC requires protein expression of the α\(_1\)- and β\(_1\)-subunits. Inflammation of the periodontium induces the resorption of cementum by cementoclasts and the resorption of the alveolar bone by osteoclasts, which can lead to tooth loss. As the presence of sGC in cementoclasts is unknown, we investigated the α\(_1\)- and β\(_1\)-subunits of sGC in cementoclasts of healthy and inflamed human periodontium using double immunostaining for CD68 and cathepsin K and compared the findings with those of osteoclasts from the same sections. In comparison to cementoclasts in the healthy periodontium, cementoclasts under inflammatory conditions showed a decreased staining intensity for both α\(_1\)- and β\(_1\)-subunits of sGC, indicating reduced protein expression of these subunits. Therefore, pharmacological activation of sGC in inflamed periodontal tissues in an NO- and heme-independent manner could be considered as a new treatment strategy to inhibit cementum resorption. KW - nitric oxide KW - soluble guanylyl cyclase KW - cGMP KW - cementoclasts KW - cementum KW - osteoclasts KW - alveolar bone KW - periodontitis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285783 SN - 1422-0067 VL - 22 IS - 2 ER - TY - JOUR A1 - Hoffmann, Linda S. A1 - Etzrodt, Jennifer A1 - Willkomm, Lena A1 - Sanyal, Abhishek A1 - Scheja, Ludger A1 - Fischer, Alexander W. C. A1 - Stasch, Johannes-Peter A1 - Bloch, Wilhelm A1 - Friebe, Andreas A1 - Heeren, Joerg A1 - Pfeifer, Alexander T1 - Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue JF - Nature Communications N2 - Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) combusts energy to produce heat. Here we show that a small molecule stimulator (BAY 41-8543) of soluble guanylyl cyclase (sGC), which produces the second messenger cyclic GMP (cGMP), protects against diet-induced weight gain, induces weight loss in established obesity, and also improves the diabetic phenotype. Mechanistically, the haeme-dependent sGC stimulator BAY 41-8543 enhances lipid uptake into BAT and increases whole-body energy expenditure, whereas ablation of the haeme-containing \(\beta\)\(_{1}\)-subunit of sGC severely impairs BAT function. Notably, the sGC stimulator enhances differentiation of human brown adipocytes as well as induces 'browning' of primary white adipocytes. Taken together, our data suggest that sGC is a potential pharmacological target for the treatment of obesity and its comorbidities. KW - decompensated heart failure KW - mitochondrial biogenesis KW - pulmonary hypertension KW - nitric oxide KW - erectile dysfunction KW - beige adipocytes KW - fat development KW - cGMP KW - riociguat KW - white Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143127 VL - 6 IS - 7235 ER - TY - JOUR A1 - Gambaryan, Stepan A1 - Subramanian, Hariharan A1 - Kehrer, Linda A1 - Mindukshev, Igor A1 - Sudnitsyna, Julia A1 - Reiss, Cora A1 - Rukoyatkina, Natalia A1 - Friebe, Andreas A1 - Sharina, Iraida A1 - Martin, Emil A1 - Walter, Ulrich T1 - Erythrocytes do not activate purified and platelet soluble guanylate cyclases even in conditions favourable for NO synthesis JF - Cell Communication and Signaling N2 - Background Direct interaction between Red blood cells (RBCs) and platelets is known for a long time. The bleeding time is prolonged in anemic patients independent of their platelet count and could be corrected by transfusion of RBCs, which indicates that RBCs play an important role in hemostasis and platelet activation. However, in the last few years, opposing mechanisms of platelet inhibition by RBCs derived nitric oxide (NO) were proposed. The aim of our study was to identify whether RBCs could produce NO and activate soluble guanylate cyclase (sGC) in platelets. Methods To test whether RBCs could activate sGC under different conditions (whole blood, under hypoxia, or even loaded with NO), we used our well-established and highly sensitive models of NO-dependent sGC activation in platelets and activation of purified sGC. The activation of sGC was monitored by detecting the phosphorylation of Vasodilator Stimulated Phosphoprotein (VASPS239) by flow cytometry and Western blot. ANOVA followed by Bonferroni’s test and Student’s t-test were used as appropriate. Results We show that in the whole blood, RBCs prevent NO-mediated inhibition of ADP and TRAP6-induced platelet activation. Likewise, coincubation of RBCs with platelets results in strong inhibition of NO-induced sGC activation. Under hypoxic conditions, incubation of RBCs with NO donor leads to Hb-NO formation which inhibits sGC activation in platelets. Similarly, RBCs inhibit activation of purified sGC, even under conditions optimal for RBC-mediated generation of NO from nitrite. Conclusions All our experiments demonstrate that RBCs act as strong NO scavengers and prevent NO-mediated inhibition of activated platelets. In all tested conditions, RBCs were not able to activate platelet or purified sGC. KW - hemoglobin KW - erythrocytes KW - nitric oxide KW - soluble guanylate cyclase KW - platelets Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161223 VL - 14 IS - 16 ER - TY - JOUR A1 - Dandekar, Thomas A1 - Fieselmann, Astrid A1 - Fischer, Eva A1 - Popp, Jasmin A1 - Hensel, Michael A1 - Noster, Janina T1 - Salmonella - how a metabolic generalist adopts an intracellular lifestyle during infection JF - Frontiers in Cellular and Infection Microbiology N2 - The human-pathogenic bacterium Salmonella enterica adjusts and adapts to different environments while attempting colonization. In the course of infection nutrient availabilities change drastically. New techniques, "-omics" data and subsequent integration by systems biology improve our understanding of these changes. We review changes in metabolism focusing on amino acid and carbohydrate metabolism. Furthermore, the adaptation process is associated with the activation of genes of the Salmonella pathogenicity islands (SPIs). Anti-infective strategies have to take these insights into account and include metabolic and other strategies. Salmonella infections will remain a challenge for infection biology. KW - enterica serovar Typhimurium KW - bacterial invasion KW - mouse model KW - defenses KW - regulation KW - "-omics" KW - virulence KW - Salmonella-containing vacuole (SCV) KW - metabolism KW - nitric oxide Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149029 VL - 4 IS - 191 ER -