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mtDNA haplogroup J Modulates telomere length and Nitric Oxide production
Mercedes Fernández-Moreno, María Tamayo, Angel Soto-Hermida, Alejandro Mosquera, Natividad Oreiro, Carlos Fernández-López, José Luis Fernández, Ignacio Rego-Pérez, Francisco J Blanco
BMC Musculoskeletal Disorders , 2011, DOI: 10.1186/1471-2474-12-283
Abstract: The telomere length of PBL was analyzed in DNA samples from 166 healthy controls (114 J and 52 non-J) and 79 OA patients (41 J and 38 non-J) by means of a validated qPCR method. The NO production was assessed in 7 carriers of the haplogroup J and 27 non-J carriers, by means of the colorimetric reaction of the Griess reagent in supernatants of cultured chondrocytes. Inducible nitric oxide synthase (iNOS) mRNA from these samples was analyzed by qPCR. Appropiated statistical analyses were performedCarriers of the haplogroup J showed a significantly longer telomere length of PBLs than non-J carriers, regardless of age, gender and diagnosis (p = 0.025). Cultured chondrocytes carrying the mtDNA haplogroup J also showed a lower NO production than non-J carriers (p = 0.043). No significant correlations between age and telomore length of PBLs were detected neither for carriers of the haplogroup J nor for non-J carriers. A strong positive correlation between NO production and iNOS expression was also observed (correlation coefficient = 0.791, p < 0.001).The protective effect of the mtDNA haplogroup J in the OA disease arise from a lower oxidative stress in carriers of this haplogroup, since this haplogroup is related to lower NO production and hence longer telomere length of PBLs too.Osteoarthritis (OA), the most common form of joint disease and cause of musculoskeletal disability in elderly people, is a disease affecting articular cartilage, bone and soft tissue leading to joint destruction and severe impairment of mobility [1]. It is also the main cause of work incapacity and one of the most common reasons for visiting primary physicians. The metabolic and structural changes that take place in the articular cartilage, including the reactive oxygen and nitrogen species (RONS), are thought to play a main role in the initiation and progression of this disease.A growing body of evidence suggests that oxidative damage, due to the overproduction of nitric oxide (NO) and other rea
Reactive oxygen species induce expression of vascular endothelial growth factor in chondrocytes and human articular cartilage explants
Jakob Fay, Deike Varoga, Christoph J Wruck, Bodo Kurz, Mary B Goldring, Thomas Pufe
Arthritis Research & Therapy , 2006, DOI: 10.1186/ar2102
Abstract: Aspirates of synovial fluid from patients with osteoarthritis (OA) were examined for intra-articular VEGF using ELISA. Immortalized C28/I2 chondrocytes and human knee cartilage explants were exposed to phorbol myristate acetate (PMA; 0–20 μg/ml), which is a ROS inducer, or 3-morpholino-sydnonimine hydrochloride (SIN-1; 0–20 μM), which is a ROS donor. The levels of VEGF protein and nitric oxide (NO) production were determined in the medium supernatant, using ELISA and Griess reagent, respectively. Gene expression of VEGF-121 and VEGF-165 was determined by splice variant RT-PCR. Expression of VEGF and VEGF receptors (VEGFR-1 and VEGFR-2) was quantified by real-time RT-PCR.Synovial fluid from OA patients revealed markedly elevated levels of VEGF. Common RT-PCR revealed that the splice variants were present in both immortalized chondrocytes and cartilage discs. In immortalized chondrocytes, stimulation with PMA or SIN-1 caused increases in the levels of VEGF, VEGFR-1 and VEGFR-2 mRNA expression. Cartilage explants produced similar results, but VEGFR-1 was only detectable after stimulation with SIN-1. Stimulation with PMA or SIN-1 resulted in a dose-dependent upregulation of the VEGF protein (as determined using ELISA) and an increase in the level of NO in the medium.Our findings indicate ROS-mediated induction of VEGF and VEGF receptors in chondrocytes and cartilage explants. These results demonstrate a relationship between ROS and VEGF as multiplex mediators in articular cartilage degeneration.Osteoarthritis (OA) is characterized by a breakdown of the extracellular matrix (ECM) of articular cartilage in the affected joints. The pathogenesis of OA involves multiple aetiologies, including mechanical, genetic and biochemical factors. However, the precise signalling pathways in the degradation of articular cartilage ECM and development of OA are still not fully understood. Several studies have demonstrated the involvement of cytokines, such as IL-1 and IL-6, or tumour necr
Nitric Oxide-Driven Hypoxia Initiates Synovial Angiogenesis, Hyperplasia and Inflammatory Lesions in Mice  [PDF]
Fei Bao, Pei Wu, Na Xiao, Frank Qiu, Qing-Ping Zeng
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034494
Abstract: Background Rheumatoid arthritis (RA) is an inflammatory articular disease with cartilage and bone damage due to hyperplasic synoviocyte invasion and subsequent matrix protease digestion. Although monoclonal antibodies against tumor necrosis factor alpha (TNFα) have been approved for clinical use in patients with RA, desired therapeutic regimens suitable for non-responders are still unavailable because etiological initiators leading to RA remain enigmatic and unidentified. Methodology/Principal Findings Bacteria-induced arthritis (BIA) that simulates collagen-induced arthritis (CIA) is developed in mice upon daily live bacterial feeding. The morphological lesions of paw erythema and edema together with the histological alterations of synovial hyperplasia and lymphocytic infiltration emerge as the early-phase manifestations of BIA and CIA. Bacteria- or collagen-mediated global upregulation of pro-inflammatory cytokines is accompanied by the burst of nitric oxide (NO). Elevation of the serum NO level is correlated with decline of the blood oxygen saturation percentage (SpO2), reflecting a hypoxic consequence during development towards arthritis. NO-driven hypoxia is further evident from a positive relationship between NO and lactic acid (LA), an end product from glycolysis. Upregulation of hypoxia inducible factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) validates hypoxia-induced angiogenesis in the inflamed synovium of modeling mice. Administration of the NO donor compound sodium nitroprusside (SNP) causes articular inflammation by inducing synovial hypoxia. Anti-bacteria by the antibiotic cefotaxime and/or the immunosuppressant rapamycin or artesunate that also inhibits nitric oxide synthase (NOS) can abrogate NO production, mitigate hypoxia, and considerably ameliorate or even completely abort synovitis, hence highlighting that NO may serve as an initiator of inflammatory arthritis. Conclusions/Significance Like collagen, bacteria also enable synovial lesions via upregulating pro-inflammatory cytokines, triggering NO production, driving hypoxic responses, and inducing synovial angiogenesis and hyperplasia, suggesting that sustained infection might be, in part, responsible for the onset of synovitis and arthritis in mice.
Therapeutic Gases: Oxygen, Carbondiokside, Nitric Oxide and Helium  [PDF]
A?k?n Hekimo?lu
Dicle Medical Journal , 2007,
Abstract: This review is about the structures of commonly used therapeutic gases Oxygen, Carbondiokside, Nitric Oxide and Helium. Their structures, effects on physiological systems, toxicities, usage indications and methods are presented.
Coenzyme Q10 Ameliorates Pain and Cartilage Degradation in a Rat Model of Osteoarthritis by Regulating Nitric Oxide and Inflammatory Cytokines  [PDF]
Jennifer Lee, Yeon Sik Hong, Jeong Hee Jeong, Eun Ji Yang, Joo Yeon Jhun, Mi Kyoung Park, Young Ok Jung, Jun Ki Min, Ho Youn Kim, Sung Hwan Park, Mi-La Cho
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069362
Abstract: Objective To investigate the effect of CoenzymeQ10 (CoQ10) on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA). Materials and Methods OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration of CoQ10 was initiated on day 4 after MIA injection. Pain severity was assessed by measuring secondary tactile allodynia using the von Frey assessment test. The degree of cartilage degradation was determined by measuring cartilage thickness and the amount of proteoglycan. The mankin scoring system was also used. Expressions of matrix metalloproteinase-13 (MMP-13), interleukin-1β (IL-1β), IL-6, IL-15, inducible nitric oxide synthase (iNOS), nitrotyrosine and receptor for advanced glycation end products (RAGE) were analyzed using immunohistochemistry. Results Treatment with CoQ10 demonstrated an antinociceptive effect in the OA animal model. The reduction in secondary tactile allodynia was shown by an increased pain withdrawal latency and pain withdrawal threshold. CoQ10 also attenuated cartilage degeneration in the osteoarthritic joints. MMP-13, IL-1β, IL-6, IL-15, iNOS, nitrotyrosine and RAGE expressions were upregulated in OA joints and significantly reduced with CoQ10 treatment. Conclusion CoQ10 exerts a therapeutic effect on OA via pain suppression and cartilage degeneration by inhibiting inflammatory mediators, which play a vital role in OA pathogenesis.
Nitric Oxide: Oxygen Radical Interactions in Atherosclerosis
RUBBO,HOMERO; BATTHYANY,CARLOS; RADI,RAFAEL;
Biological Research , 2000, DOI: 10.4067/S0716-97602000000200017
Abstract: atherosclerosis is one of the most common diseases and the principal cause of death in western civilization. the pathogenesis of this disease can be explained on the basis of the ?oxidative-modification hypothesis,? which proposes that low-density lipoprotein (ldl) oxidation represents a key early event. nitric oxide (.no) regulates critical lipid membrane and lipoprotein oxidation events by a) contributing to the formation of more potent secondary oxidants from superoxide (i.e.: peroxynitrite), and b) its antioxidant properties through termination reactions with lipid radicals to possibly less reactive secondary nitrogen-containing products (lono, loono). relative rates of production and steady state concentrations of superoxide and .no and cellular sites of production will profoundly influence the expression of differential oxidant injury-enhancing and protective effects of .no. full understanding of the physiological roles of .no, coupled with detailed insight into .no regulation of oxygen radical-dependent reactions, will yield a more rational basis for intervention strategies directed toward oxidant-dependent atherogenic processes
Nitric Oxide: Oxygen Radical Interactions in Atherosclerosis  [cached]
HOMERO RUBBO,CARLOS BATTHYANY,RAFAEL RADI
Biological Research , 2000,
Abstract: Atherosclerosis is one of the most common diseases and the principal cause of death in western civilization. The pathogenesis of this disease can be explained on the basis of the ‘oxidative-modification hypothesis,’ which proposes that low-density lipoprotein (LDL) oxidation represents a key early event. Nitric oxide (.NO) regulates critical lipid membrane and lipoprotein oxidation events by a) contributing to the formation of more potent secondary oxidants from superoxide (i.e.: peroxynitrite), and b) its antioxidant properties through termination reactions with lipid radicals to possibly less reactive secondary nitrogen-containing products (LONO, LOONO). Relative rates of production and steady state concentrations of superoxide and .NO and cellular sites of production will profoundly influence the expression of differential oxidant injury-enhancing and protective effects of .NO. Full understanding of the physiological roles of .NO, coupled with detailed insight into .NO regulation of oxygen radical-dependent reactions, will yield a more rational basis for intervention strategies directed toward oxidant-dependent atherogenic processes
Reactive Oxygen Species and Nitric Oxide in Cutaneous Leishmaniasis  [PDF]
Maria Fátima Horta,Bárbara Pinheiro Mendes,Eric Henrique Roma,Fátima Soares Motta Noronha,Juan Pereira Macêdo,Luciana Souza Oliveira,Myrian Morato Duarte,Leda Quercia Vieira
Journal of Parasitology Research , 2012, DOI: 10.1155/2012/203818
Abstract: Cutaneous leishmaniasis affects millions of people around the world. Several species of Leishmania infect mouse strains, and murine models closely reproduce the cutaneous lesions caused by the parasite in humans. Mouse models have enabled studies on the pathogenesis and effector mechanisms of host resistance to infection. Here, we review the role of nitric oxide (NO), reactive oxygen species (ROS), and peroxynitrite (ONOO?) in the control of parasites by macrophages, which are both the host cells and the effector cells. We also discuss the role of neutrophil-derived oxygen and nitrogen reactive species during infection with Leishmania. We emphasize the role of these cells in the outcome of leishmaniasis early after infection, before the adaptive Th-cell immune response. 1. Introduction More than 20 Leishmania species cause leishmaniasis in people with different genetic backgrounds and general states of health. Further, the diversity of clinical manifestations, epidemiology, and immunopathology makes leishmaniasis a complex disease to study. Clinical manifestations include ulcerative skin lesions, destructive mucosal inflammation, and disseminated visceral infection (kala azar). Morbidity includes disfigurement and disability. However, some features are shared by all forms of infection by these protozoan parasites: parasitism is persistent, tissue macrophages are the main parasitized cell, and the host immune response defines the outcome of the disease [1]. Cutaneous leishmaniasis is caused by several species of the genus Leishmania, including L. major, L. tropica, L. aethiopica, L. mexicana, L. braziliensis, L. guyanensis, L. panamensis, L. peruviana, and L. amazonensis. The Leishmania genus is divided in two subgenera, Leishmania and Viannia. In the subgenus Leishmania, L. amazonensis, L. mexicana (complex L. mexicana), and L. major (complex L. major) are by far the most studied species that cause cutaneous leishmaniasis. The subgenus Viannia comprises two important species that cause cutaneous leishmaniasis, L. guyanensis (complex L. guyanensis) and L. braziliensis (complex L. braziliensis) [2, 3]. The promastigote stage of the parasite lives in the gut of sandflies (Phlebotomus in the Old World and Lutzomyia in the New World) [4]. In the insect gut, Leishmania promastigotes develop into metacyclic (infective) forms and enter the vertebrate host when female sandflies take a blood meal. In the vertebrate host, phagocytic cells ingest the metacyclic promastigotes that, inside the phagolysosome, differentiate into the amastigote form and replicate. The
Nitric oxide mediates interleukin-1 induced inhibition of glycosaminoglycan synthesis in rat articular cartilage  [cached]
T. A. H. Järvinen,T. Moilanen,T. L. N. Järvinen,E. Moilanen
Mediators of Inflammation , 1995, DOI: 10.1155/s0962935195000184
Abstract:
Hsp90β inhibition modulates nitric oxide production and nitric oxide-induced apoptosis in human chondrocytes
Valentina Calamia, Maria C de Andrés, Natividad Oreiro, Cristina Ruiz-Romero, Francisco J Blanco
BMC Musculoskeletal Disorders , 2011, DOI: 10.1186/1471-2474-12-237
Abstract: Human OA chondrocytes were isolated from cartilage obtained from patients undergoing joint replacement surgery, and primary cultured. Cells were stimulated with proinflammatory cytokines (IL-1β or TNF-α) and nitric oxide donors (NOC-12 or SNP). For Hsp90β inhibition, two different chemical inhibitors (Geldanamycin and Novobiocin) were employed, or siRNA transfection procedures were carried out. Gene expression was determined by real-time PCR, apoptosis was quantified by flow cytometry and ELISA, and nitric oxide (NO) production was evaluated by the Griess method. Indirect immunofluorescence assays were performed to evaluate the presence of Hsp90β in stimulated cells.Hsp90β was found to be increased by proinflammatory cytokines. Inhibition of Hsp90β by the chemicals Geldanamycin (GA) and Novobiocin (NB) caused a dose-dependent decrease of the NO production induced by IL-1β in chondrocytes, up to basal levels. Immunofluorescence analyses demonstrate that the NO donors NOC-12 and SNP also increased Hsp90β. Chemical inhibition or specific gene silencing of this chaperone reduced the DNA condensation and fragmentation, typical of death by apoptosis, that is induced by NO donors in chondrocytes.The present results show how Hsp90β modulates NO production and NO-mediated cellular death in human OA chondrocytes.Osteoarthritis (OA) is a slowly progressive degenerative disease characterized by the degradation of the extracellular matrix (ECM) and cell death, resulting in a gradual loss of articular cartilage integrity, intra-articular inflammation and changes in peri-articular and subchondral bone [1]. The chondrocyte is the only cell type present in mature cartilage and is responsible for repairing the cartilage tissue damaged by OA.Chondrocytes are key players in the control of cartilage matrix turnover through the production and secretion of collagens, proteoglycans, and enzymes affecting cartilage metabolism [2]. Chondrocyte metabolism is influenced by several cytokines an
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