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Abstract Background Chronic therapy with nitroglycerin (GTN) results in a rapid development of nitrate tolerance which is associated with an increased production of reactive oxygen species (ROS). According to recent studies, mitochondrial ROS formation and oxidative inactivation of the organic nitrate bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) play an important role for the development of nitrate and cross-tolerance. Methods Tolerance was induced by infusion of wild type (WT) and heterozygous manganese superoxide dismutase mice (Mn-SOD+/-) with ethanolic solution of GTN (12.5 μg/min/kg for 4 d). For comparison, the tolerance-free pentaerithrityl tetranitrate (PETN, 17.5 μg/min/kg for 4 d) was infused in DMSO. Vascular reactivity was measured by isometric tension studies of isolated aortic rings. ROS formation and aldehyde dehydrogenase (ALDH-2) activity was measured in isolated heart mitochondria. Results Chronic GTN infusion lead to impaired vascular responses to GTN and acetylcholine (ACh), increased the ROS formation in mitochondria and decreased ALDH-2 activity in Mn-SOD+/- mice. In contrast, PETN infusion did not increase mitochondrial ROS formation, did not decrease ALDH-2 activity and accordingly did not lead to tolerance and cross-tolerance in Mn-SOD+/- mice. PETN but not GTN increased heme oxygenase-1 mRNA in EA.hy 926 cells and bilirubin efficiently scavenged GTN-derived ROS. Conclusion Chronic GTN infusion stimulates mitochondrial ROS production which is an important mechanism leading to tolerance and cross-tolerance. The tetranitrate PETN is devoid of mitochondrial oxidative stress induction and according to the present animal study as well as numerous previous clinical studies can be used without limitations due to tolerance and cross-tolerance.

Increased concentrations of reactive oxygen species (ROS) originating from dysfunctional mitochondria contribute to diverse aging-related degenerative disorders. But so far little is known about the impact of distinct ROS on metabolism and fate of stromal precursor cells. Here, we demonstrate that an increase in superoxide anion radicals due to superoxide dismutase 2 (Sod2) deficiency in stromal precursor cells suppress osteogenic and adipogenic differentiation through fundamental changes in the global metabolite landscape. Our data identify impairment of the pyruvate and l-glutamine metabolism causing toxic accumulation of alpha-ketoglutarate in the Sod2-deficient and intrinsically aged stromal precursor cells as a major cause for their reduced lineage differentiation. Alpha-ketoglutarate accumulation led to enhanced nucleocytoplasmic vacuolation and chromatin condensation-mediated cell death in Sod2-deficient stromal precursor cells as a consequence of DNA damage, Hif-1α instability, and reduced histone H3 (Lys27) acetylation. These findings hold promise for prevention and treatment of mitochondrial disorders commonly associated with aged individuals. S tem C ells 2017;35:1704-1718 [ABSTRACT FROM AUTHOR]

The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions ( [ABSTRACT FROM AUTHOR]

The free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. The skin represents an excellent and accessible model organ to study aging that is characterized by atrophy, wrinkle formation, reduced tensile strength and impaired wound healing. Oxidative stress as a consequence of an imbalance in prooxidants and antioxidants with increased ROS concentrations has been demonstrated in the aged skin in vitro and in vivo, suggesting the important role of the antioxidant balance. Here we will summarize recent data on the role of the mitochondrial superoxide dismutase 2 in skin aging. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are involved in both bone and cartilage physiology and play an important role in the pathogenesis of osteoporosis and osteoarthritis. The present study investigated the effect of running exercise on bone and cartilage in heterozygous manganese superoxide dismutase (SOD2)-deficient mice. It was hypothesized that exercise might induce an increased production of ROS in these tissues. Heterozygous SOD2-deficient mice should exhibit an impaired capability to compensate, resulting in an increased oxidative stress in cartilage and bone. Thirteen female wild type and 20 SOD2++/−− mice (aged 16 weeks) were randomly assigned to a non-active wild type (SOD2++/++Con, n == 7), a trained wild type (SOD2++/++Run, n == 6), a non-active SOD2++/−− (SOD2++/−−Con, n == 9) and a trained SOD2++/−− (SOD2++/−−Run, n == 11) group. Training groups underwent running exercise on a treadmill for 8 weeks. In SOD2++/−− mice elevated levels of 15-F2t-isoprostane and nitrotyrosine were detected in bone and articular cartilage compared to wild type littermates. In osteocytes the elevated levels of these molecules were found to be reduced after exercise while in chondrocytes they were increased by aerobic running exercise. The observed changes in oxidative and nitrosative stress did neither affect morphological, structural nor mechanical properties of both tissues. These results demonstrate that exercise might protect bone against oxidative stress in heterozygous SOD2-deficient mice. [ABSTRACT FROM AUTHOR]

Background: Chronic therapy with nitroglycerin (GTN) results in a rapid development of nitrate tolerance which is associated with an increased production of reactive oxygen species (ROS). According to recent studies, mitochondrial ROS formation and oxidative inactivation of the organic nitrate bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) play an important role for the development of nitrate and cross-tolerance. Methods: Tolerance was induced by infusion of wild type (WT) and heterozygous manganese superoxide dismutase mice (Mn-SOD+/-) with ethanolic solution of GTN (12.5 µg/min/kg for 4 d). For comparison, the tolerance-free pentaerithrityl tetranitrate (PETN, 17.5 µg/min/kg for 4 d) was infused in DMSO. Vascular reactivity was measured by isometric tension studies of isolated aortic rings. ROS formation and aldehyde dehydrogenase (ALDH-2) activity was measured in isolated heart mitochondria. Results: Chronic GTN infusion lead to impaired vascular responses to GTN and acetylcholine (ACh), increased the ROS formation in mitochondria and decreased ALDH-2 activity in Mn-SOD+/- mice. In contrast, PETN infusion did not increase mitochondrial ROS formation, did not decrease ALDH-2 activity and accordingly did not lead to tolerance and cross-tolerance in Mn-SOD+/- mice. PETN but not GTN increased heme oxygenase-1 mRNA in EA.hy 926 cells and bilirubin efficiently scavenged GTN-derived ROS. Conclusion: Chronic GTN infusion stimulates mitochondrial ROS production which is an important mechanism leading to tolerance and cross-tolerance. The tetranitrate PETN is devoid of mitochondrial oxidative stress induction and according to the present animal study as well as numerous previous clinical studies can be used without limitations due to tolerance and cross-tolerance. [ABSTRACT FROM AUTHOR]

Background and Objectives: The question of how frequently patients with medium to high-risk melanomas become aware of their tumors and which self-detection patterns exist remains unanswered., Patients and Methods: We conducted a retrospective survey of melanoma patients who had undergone sentinel node biopsy between 2004 and 2008. One hundred twenty-seven out of a total of 133 patients completed the questionnaire., Results: Twenty-five percent of patients had not noticed their tumors at all. The remaining 75 % showed three different self-detection patterns, with 25 % of individuals seeking medical advice within 0-12 weeks and another 25 % within 3-6 months. The remaining 25 % had waited for more than six months prior to tumor excision. Age, gender, and melanoma location were comparable in all self-detection subgroups. The most frequent subtypes were: SSM (59), NMM (31), ALM (9), UCM (9) and LMM (4). Rare subtypes occurred in 15 individuals. Patients with lesions previously noticed for 3-6 months revealed the highest average tumor thickness and the significantly highest number of pT4 tumors. Sixty percent of NMM patients had a disease history < 6 months. Rare subtypes such as amelanotic, spindle cell, or spitzoid melanoma were self-detected in only 50 % of cases., Conclusions: Even advanced melanoma lesions remained undetected in 25 % of patients; rare melanoma subtypes, in 50 % of cases. Thus, self-examination frequency, increased awareness of rare melanoma subtypes, and rapid referral to a specialist ought to be at the center of future awareness campaigns., (© 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Hintergrund Und Zielsetzung: Die Frage, wie oft Melanompatienten mit Mittel- bis Hochrisikomelanomen den Tumor bemerken und welche Eigenerkennungsmuster existieren ist bislang nicht beantwortet., Patienten Und Methoden: Wir haben eine retrospektive Studie an Melanompatienten durchgeführt, die sich zwischen 2004 und 2008 einer Sentinellymphknotenbiopsie unterzogen haben,. Der Fragebogen wurde von 127 der insgesamt 133 Patienten ausgefüllt., Ergebnisse: 25 % bemerkten den Tumor überhaupt nicht. Die restlichen 75 % zeigten verschiedene Eigenerkennungsmuster: 25 % holten nach 0-12 Wochen Rat ein, weitere 25 % innerhalb von 3-6 Monaten, und bei den restlichen 25 % wurde der Tumor mehr als sechs Monate lang beobachtet, bevor er entfernt wurde. Alter, Geschlecht und Lokalisation des Melanoms waren bei allen Eigenerkennungsgruppen vergleichbar. Die häufigsten Subtypen waren: SSM (59), NMM (31), ALM (9), UCM (9) und LMM (4). Seltene Subtypen (15) waren ebenfalls vorhanden. Patienten mit 3-6 Monate alten Läsionen zeigten die höchste durchschnittliche Tumordicke und die bei weitem höchste Anzahl von pT4-Tumoren. 60 % der Patienten mit NMM hatten eine Krankengeschichte von <6 Monaten. Seltene Subtypen wie amelanotische, Spindelzell- und spitzoide Melanome wurden in nur 50 % der Fälle selbstständig erkannt., Schlussfolgerungen: Selbst fortgeschrittene Melanome blieben von den Patienten in 25 %, seltene Melanom-Subtypen in 50 % der Fälle unerkannt. Daher sollte der Eigenerkennungshäufigkeit, dem erhöhten Bewusstsein für seltene Melanome und der schnellen Überweisung an einen Spezialisten in zukünftigen Aufklärungskampagnen besondere Aufmerksamkeit zukommen., (© 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Aging is associated with a rising incidence of cutaneous squamous cell carcinoma (cSCC), an aggressive skin cancer with the potential for local invasion and metastasis. Acquisition of a senescence-associated secretory phenotype (SASP) in dermal fibroblasts has been postulated to promote skin cancer progression in elderly individuals. The underlying molecular mechanisms are largely unexplored. We show that Chemerin, a previously unreported SASP factor released from senescent human dermal fibroblasts, promotes cSCC cell migration, a key feature driving tumor progression. Whereas the Chemerin abundance is downregulated in malignant cSCC cells, increased Chemerin transcripts and protein concentrations are detected in replicative senescent fibroblasts in vitro and in the fibroblast of skin sections from old donors, indicating that a Chemerin gradient is built up in the dermis of elderly. Using Transwell® migration assays, we show that Chemerin enhances the chemotaxis of different cSCC cell lines. Notably, the Chemerin receptor CCRL2 is remarkably upregulated in cSCC cell lines and human patient biopsies. Silencing Chemerin in senescent fibroblasts or the CCRL2 and GPR1 receptors in the SCL-1 cSCC cell line abrogates the Chemerin-mediated chemotaxis. Chemerin triggers the MAPK cascade via JNK and ERK1 activation, whereby the inhibition impairs the SASP- or Chemerin-mediated cSCC cell migration.Taken together, we uncover a key role for Chemerin, as a major factor in the secretome of senescent fibroblasts, promoting cSCC cell migration and possibly progression, relaying its signals through CCRL2 and GPR1 receptors with subsequent MAPK activation. These findings might have implications for targeted therapeutic interventions in elderly patients.

Nitroglycerin (GTN)-induced tolerance was reported to be associated with increased levels of reactive oxygen species (ROS) in mitochondria. In the present study, we further investigated the role of ROS for the development of nitrate tolerance by using heterozygous manganese superoxide dismutase knock-out mice (Mn-SOD+/-). Mn-SOD is acknowledged as a major sink for mitochondrial superoxide. Vasodilator potency of mouse aorta in response to acetylcholine and GTN was assessed by isometric tension studies. Mitochondrial ROS formation was detected by 8-amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)dione sodium salt (L-012)-enhanced chemiluminescence and mitochondrial aldehyde dehydrogenase (ALDH-2) activity was determined by a high-performance liquid chromatography-based assay. Aortic rings from Mn-SOD+/- mice showed normal endothelial function and vasodilator responses to GTN. In contrast, preincubation of aorta with GTN or long-term GTN infusion caused a marked higher degree of tolerance as well as endothelial dysfunction in Mn-SOD+/- compared with wild type. Basal as well as GTN-stimulated ROS formation was significantly increased in isolated heart mitochondria from Mn-SOD+/- mice, correlating well with a marked decrease in ALDH-2 activity in response to in vitro and in vivo GTN treatment. The data presented indicate that deficiency in Mn-SOD leads to a higher degree of tolerance and endothelial dysfunction associated with increased mitochondrial ROS production in response to in vitro and in vivo GTN challenges. These data further point to a crucial role of ALDH-2 in mediating GTN bioactivation as well as development of GTN tolerance and underline the important contribution of ROS to these processes.

The transcription factor C/EBPalpha is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and C/EBPalpha can block 12-O-tetradecanoylphorbol-13-acetate-induced monocytic differentiation of bipotential myeloid cells. In C/EBPalpha knockout mice, no mature granulocytes are present. A dramatic increase of c-Jun mRNA in C/EBPalpha knockout mouse fetal liver was observed. c-Jun, a component of the AP-1 transcription factor complex and a coactivator of the transcription factor PU.1, is important for monocytic differentiation. Here we report that C/EBPalpha downregulates c-Jun expression to drive granulocytic differentiation. An ectopic increase of C/EBPalpha expression decreases the c-Jun mRNA level, and the human c-Jun promoter activity is downregulated eightfold in the presence of C/EBPalpha. C/EBPalpha and c-Jun interact through their leucine zipper domains, and this interaction prevents c-Jun from binding to DNA. This results in downregulation of c-Jun's capacity to autoregulate its own promoter through the proximal AP-1 site. Overexpression of c-Jun prevents C/EBPalpha-induced granulocytic differentiation. Thus, we propose a model in which C/EBPalpha needs to downregulate c-Jun expression and transactivation capacity for promoting granulocytic differentiation.