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[Ru(bpy)2(NO)SO3](PF6), a Nitric Oxide Donating Ruthenium Complex, Reduces Gout Arthritis in Mice.

ABSTRACT: Monosodium urate crystals (MSU) deposition induces articular inflammation known as gout. This disease is characterized by intense articular inflammation and pain by mechanisms involving the activation of the transcription factor NF?B and inflammasome resulting in the production of cytokines and oxidative stress. Despite evidence that MSU induces iNOS expression, there is no evidence on the effect of nitric oxide (NO) donors in gout. Thus, the present study evaluated the effect of the ruthenium complex donor of NO {[Ru(bpy)2(NO)SO3](PF6)} (complex I) in gout arthritis. Complex I inhibited in a dose-dependent manner MSU-induced hypersensitivity to mechanical stimulation, edema and leukocyte recruitment. These effects were corroborated by a decrease of histological inflammation score and recruitment of Lysm-eGFP+ cells. Mechanistically, complex I inhibited MSU-induced mechanical hypersensitivity and joint edema by triggering the cGMP/PKG/ATP-sensitive K (+) channels signaling pathway. Complex I inhibited MSU-induced oxidative stress and pro-inflammatory cytokine production in the knee joint. These data were supported by the observation that complex I inhibited MSU-induced NF?B activation, and IL-1? expression and production. Complex I also inhibited MSU-induced activation of pro-IL-1? processing. Concluding, the present data, to our knowledge, is the first evidence that a NO donating ruthenium complex inhibits MSU-induced articular inflammation and pain. Further, complex I targets the main physiopathological mechanisms of gout arthritis. Therefore, it is envisaged that complex I and other NO donors have therapeutic potential that deserves further investigation.

SUBMITTER: Rossaneis AC

PROVIDER: S-EPMC6423075 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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[Ru(bpy)2(NO)SO3](PF6), a Nitric Oxide Donating Ruthenium Complex, Reduces Gout Arthritis in Mice.

Rossaneis Ana C AC Longhi-Balbinot Daniela T DT Bertozzi Mariana M MM Fattori Victor V Segato-Vendrameto Carina Z CZ Badaro-Garcia Stephanie S Zaninelli Tiago H TH Staurengo-Ferrari Larissa L Borghi Sergio M SM Carvalho Thacyana T TT Bussmann Allan J C AJC Gouveia Florêncio S FS Lopes Luiz G F LGF Casagrande Rubia R Verri Waldiceu A WA

Frontiers in pharmacology 20190312

Monosodium urate crystals (MSU) deposition induces articular inflammation known as gout. This disease is characterized by intense articular inflammation and pain by mechanisms involving the activation of the transcription factor NFκB and inflammasome resulting in the production of cytokines and oxidative stress. Despite evidence that MSU induces iNOS expression, there is no evidence on the effect of nitric oxide (NO) donors in gout. Thus, the present study evaluated the effect of the ruthenium c ...[more]

PMID: 30914954

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Project description:BackgroundNitric oxide-releasing drugs are used for cardiovascular diseases; however, their effects on the tumor immune microenvironment are less clear. Therefore, this study explored the impact of nitric oxide donors on tumor progression in immune-competent mice.MethodsThe effects of three different nitric oxide-releasing compounds (SNAP, SNP, and ISMN) on tumor growth were studied in tumor-bearing mouse models. Three mouse tumor models were used: B16F1 melanoma and LL2 lung carcinoma in C57BL/6 mice, CT26 colon cancer in BALB/c mice, and LL2 lung carcinoma in NOD/SCID mice. After nitric oxide treatment, splenic cytokines and lymphocytes were analyzed by cytokine array and flow cytometry, and tumor-infiltrating lymphocytes in the TME were analyzed using flow cytometry and single-cell RNA sequencing.ResultsLow doses of three exogenous nitric oxide donors inhibited tumor growth in two immunocompetent mouse models but not in NOD/SCID immunodeficient mice. Low-dose nitric oxide donors increase the levels of splenic cytokines IFN-γ and TNF-α but decrease the levels of cytokines IL-6 and IL-10, suggesting an alteration in Th2 cells. Nitric oxide donors increased the number of CD8+ T cells with activation gene signatures, as indicated by single-cell RNA sequencing. Flow cytometry analysis confirmed an increase in infiltrating CD8+ T cells and dendritic cells. The antitumor effect of nitric oxide donors was abolished by depletion of CD8+ T cells, indicating the requirement for CD8+ T cells. Tumor inhibition correlated with a decrease in a subtype of protumor macrophages and an increase in a subset of Arg1-positive macrophages expressing antitumor gene signatures. The increase in this subset of macrophages was confirmed by flow cytometry analysis. Finally, the combination of low-dose nitric oxide donor and cisplatin induced an additive cancer therapeutic effect in two immunocompetent animal models. The enhanced therapeutic effect was accompanied by an increase in the cells expressing the gene signature of NK cell.ConclusionsLow concentrations of exogenous nitric oxide donors inhibit tumor growth in vivo by regulating T cells and macrophages. CD8+ T cells are essential for antitumor effects. In addition, low-dose nitric oxide donors may be combined with chemotherapeutic drugs in cancer therapy in the future.

Dataset Information

[Ru(bpy)2(NO)SO3](PF6), a Nitric Oxide Donating Ruthenium Complex, Reduces Gout Arthritis in Mice.

Publications

[Ru(bpy)<sub>2</sub>(NO)SO<sub>3</sub>](PF<sub>6</sub>), a Nitric Oxide Donating Ruthenium Complex, Reduces Gout Arthritis in Mice.

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