Dual effect of nitric oxide donor on adjuvant arthritis

Gomaa, Adel A.; Elshenawy, Mohsen; Afifi, Noha A.; Mohammed, Eman A.; Thabit, Romany

doi:10.1016/j.intimp.2009.01.009

Cited by 13 publications

(6 citation statements)

References 50 publications

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“…49,50 We observed that Fum-PD NP-induced NO exerted anti-inflammatory effects in the studies presented herein. Perhaps the contradictory reports on the effects of NO in inflammatory joint disease may be reconciled by recognizing that NO likely has differential functions depending on the stage of the disease, 51 the amount of NO generated or administered, 52 and the tissues or cell types affected. 53 As α ν β 3 -targeted Fum-PD-loaded nanoparticles homed specifically to angiogenic blood vessels, the local level of NO induced/released following Fum-PD nanoparticle exposure might be quite high but likely constrained to the neoendothelial cells or their immediate vicinity.…”

Section: Discussionmentioning

confidence: 99%

“…Elevated levels of NO activity have been reported in serum, urine, and synovial fluid of RA patients. − Subsequent studies in experimental arthritis models seemed to confirm the detrimental effects of NO and the benefits of NO inhibition on disease manifestation. , On the other hand, evidence also suggests that NO can have beneficial properties, and the absence of iNOS or selective inhibition of iNOS aggravated rather than attenuated experimental arthritis. , We observed that Fum-PD NP-induced NO exerted anti-inflammatory effects in the studies presented herein. Perhaps the contradictory reports on the effects of NO in inflammatory joint disease may be reconciled by recognizing that NO likely has differential functions depending on the stage of the disease, the amount of NO generated or administered, and the tissues or cell types affected . As α ν β 3 -targeted Fum-PD-loaded nanoparticles homed specifically to angiogenic blood vessels, the local level of NO induced/released following Fum-PD nanoparticle exposure might be quite high but likely constrained to the neoendothelial cells or their immediate vicinity.…”

Section: Discussionmentioning

confidence: 99%

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Fumagillin Prodrug Nanotherapy Suppresses Macrophage Inflammatory Response via Endothelial Nitric Oxide

Zhou

Yan

et al. 2014

ACS Nano

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Antiangiogenesis has been extensively explored for the treatment of a variety of cancers and certain inflammatory processes. Fumagillin, a mycotoxin produced by Aspergillus fumigatus that binds methionine aminopeptidase 2 (MetAP-2), is a potent antiangiogenic agent. Native fumagillin, however, is poorly soluble and extremely unstable. We have developed a lipase-labile fumagillin prodrug (Fum-PD) that eliminated the photoinstability of the compound. Using αvβ3-integrin-targeted perfluorocarbon nanocarriers to deliver Fum-PD specifically to angiogenic vessels, we effectively suppressed clinical disease in an experimental model of rheumatoid arthritis (RA). The exact mechanism by which Fum-PD-loaded targeted nanoparticles suppressed inflammation in experimental RA, however, remained unexplained. We herein present evidence that Fum-PD nanotherapy indirectly suppresses inflammation in experimental RA through the local production of endothelial nitric oxide (NO). Fum-PD-induced NO activates AMP-activated protein kinase (AMPK), which subsequently modulates macrophage inflammatory response. In vivo, NO-induced AMPK activation inhibits mammalian target of rapamycin (mTOR) activity and enhances autophagic flux, as evidenced by p62 depletion and increased autolysosome formation. Autophagy in turn mediates the degradation of IkappaB kinase (IKK), suppressing the NF-κB p65 signaling pathway and inflammatory cytokine release. Inhibition of NO production by NG-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor, reverses the suppression of NF-κB-mediated inflammatory response induced by Fum-PD nanotherapy. These unexpected results uncover an activity of Fum-PD nanotherapy that may be further explored in the treatment of angiogenesis-dependent diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fumagillin Prodrug Nanotherapy Suppresses Macrophage Inflammatory Response via Endothelial Nitric Oxide

Zhou

Yan

et al. 2014

ACS Nano

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“…Similarly, a low dose of the systemically applied NO donor sodium nitroprusside decreased the severity of inflammation in CFA-induced arthritis of rats along with a reduction of mechanical hyperalgesia while higher doses aggravated both inflammation and hyperalgesia raising the possibility that changes in hyperalgesia were secondary to alterations of inflammation (237).…”

Section: Opposing Effects Of Nitric Oxide Revealed By Variation Of Exmentioning

confidence: 99%

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

Pethő

Reeh

2012

Physiological Reviews

241

200

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Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation or excitation by these substances of nociceptive nerve endings or fibers implicates generation of action potentials which then travel to the central nervous system and may induce pain sensation. Sensitization of nociceptors refers to their increased responsiveness to either thermal, mechanical, or chemical stimuli that may be translated to corresponding hyperalgesias. This review aims to give an account of the excitatory and sensitizing actions of inflammatory mediators including bradykinin, prostaglandins, thromboxanes, leukotrienes, platelet-activating factor, and nitric oxide on nociceptive primary afferent neurons. Manifestations, receptor molecules, and intracellular signaling mechanisms of the effects of these mediators are discussed in detail. With regard to signaling, most data reported have been obtained from transfected nonneuronal cells and somata of cultured sensory neurons as these structures are more accessible to direct study of sensory and signal transduction. The peripheral processes of sensory neurons, where painful stimuli actually affect the nociceptors in vivo, show marked differences with respect to biophysics, ultrastructure, and equipment with receptors and ion channels compared with cellular models. Therefore, an effort was made to highlight signaling mechanisms for which supporting data from molecular, cellular, and behavioral models are consistent with findings that reflect properties of peripheral nociceptive nerve endings. Identified molecular elements of these signaling pathways may serve as validated targets for development of novel types of analgesic drugs.

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“…Therefore, an increase of NO levels by high dose of NO donor will antagonize the action of dipyridamole. However, the effect of low dose of NO donor, was unexpected, it has similar effect to action of NO synthase inhibitor, may due to its negative feedback regulation action on iNOS activities [35,36]. Consistently, Mackenzie et al [37] investigated that NSAID linked with low dose of NO donating moiety are more effective in treatment of osteoarthritis than NSAID alone.…”

Section: Discussionmentioning

confidence: 99%

Influence of dipyridamole and its combination with NO donor or NO synthase inhibitor on adjuvant arthritis

Gomaa

Elshenawy

Afifi

et al. 2010

International Immunopharmacology

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Dual effect of nitric oxide donor on adjuvant arthritis

Cited by 13 publications

References 50 publications

Fumagillin Prodrug Nanotherapy Suppresses Macrophage Inflammatory Response via Endothelial Nitric Oxide

Fumagillin Prodrug Nanotherapy Suppresses Macrophage Inflammatory Response via Endothelial Nitric Oxide

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

Influence of dipyridamole and its combination with NO donor or NO synthase inhibitor on adjuvant arthritis

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