Abstract
High glucose-induced inflammation leads to atherosclerosis, which is considered a major cause of death in type 1 and type 2 diabetic patients. Nuclear factor-kappa B (NF-κB) plays a central role in high glucose-induced inflammation and is activated through toll-like receptors (TLRs) as well as canonical and protein kinase C-dependent (PKC) pathways. Non-toxic sulfur (NTS) and methylsulfonylmethane (MSM) are two sulfur-containing natural compounds that can induce anti-inflammation. Using Western blotting, real-time polymerase chain reaction, and flow cytometry, we found that high glucose-induced inflammation occurs through activation of TLRs. An effect of NTS and MSM on canonical and PKC-dependent NF-κB pathways was also demonstrated by western blotting. The effects of proinflammatory cytokines were investigated using a chromatin immunoprecipitation assay and enzyme-linked immunosorbent assay. Our results showed inhibition of the glucose-induced expression of TLR2 and TLR4 by NTS and MSM. These sulfur compounds also inhibited NF-κB activity through reactive oxygen species (ROS)-mediated canonical and PKC-dependent pathways. Finally, NTS and MSM inhibited the high glucose-induced expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α and binding of NF-κB protein to the DNA of proinflammatory cytokines. Together, these results suggest that NTS and MSM may be potential drug candidates for anti-inflammation therapy.
Keywords:
Canonical pathway; Diabetes; High glucose; NF-κB; PKC pathway; Proinflammatory cytokines; TLRs.
MeSH terms
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Antioxidants / pharmacology*
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Dimethyl Sulfoxide / pharmacology*
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Gene Expression Regulation
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Glucose / pharmacology*
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Humans
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Inflammation / prevention & control
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Mannitol / pharmacology
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Models, Biological
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics*
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NF-kappa B / metabolism
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Protein Kinase C-alpha / genetics
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Protein Kinase C-alpha / metabolism
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Sulfones / pharmacology*
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THP-1 Cells
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / metabolism
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / metabolism
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antioxidants
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IL1B protein, human
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IL6 protein, human
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Interleukin-1beta
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Interleukin-6
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NF-kappa B
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Reactive Oxygen Species
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Sulfones
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TLR2 protein, human
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TLR4 protein, human
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Tumor Necrosis Factor-alpha
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Mannitol
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dimethyl sulfone
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Protein Kinase C-alpha
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MAPK1 protein, human
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MAPK3 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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Glucose
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Dimethyl Sulfoxide