ObjectiveTo determine if oral infection will result in an increase in markers of inflammation that are known to augment atherogenesis.IntroductionIt is known that patients with inflammation or infection of the oral cavity have a higher risk of acquiring susceptibility and being in a state of systemic inflammation increasing their risk of having vascular abnormalities. In the present study we sought to examine if infection of the oral cavity would result in an increase in the levels of markers of atherogenesis.MethodsFour month old female Apo E mice were treated with P. Gingivitis or with vehicle for 10 days. Plasma was prepared using heparinized capillary tubes and plasma separators and was cryopreserved. Circulating levels of interleukin 6 and 13‐HODE were determined using a commercially available ELISA kit and LC‐ESIMS/MS employing a Q4000 Quadrupole system. The data were analyzed using one way ANOVA taking advantage of GraphPad Prism application.ResultsIn mice receiving the P. Gingivitis treatment the levels of circulating IL‐6 and 13‐HODE were significantly higher (p=0.011 and p=0.031, respectively). There was no difference in the levels of 20‐ HETE which is known not to increase in inflammation.ConclusionThe present study indicates that oral infection with P. Gingivitis results in increases in the levels of circulating inflammatory molecules that are known to contribute to vascular dysfunction and increased vulnerability to atherogenic reactions.
This research evaluated the impact of novel somatostatin receptor subtype‐4 (SSTR4) agonist SM‐I‐26 on microglia inflammatory activation. SSTR4 shows particular promise as a treatment target for Alzheimer's disease (AD) given its microglia and neuronal localization in the brain. A hallmark of AD progression is microgliosis, associated with inflammatory activation. A SSTR4 agonist that lessens microglial inflammatory activity could help mitigate AD progression.The selective and high affinity SSTR4 agonist SM‐I‐26 (Ki: 12nM, EC50: 17nM) was evaluated in BV2 microglia cells concurrent with inflammatory activation via lipopolysaccharide (LPS) treatment. After plating for 24hrs, cells were treated for 24hrs with SM‐I‐26 (0, 10, 1000nM) against LPS (0, 10, 100ng/mL). Nitrite (surrogate of nitric oxide, Griess assay) output in media and mRNA expression (RT‐qPCR) from cells of key inflammatory species (Tnf‐α, Il‐6, Il‐1β) were measured. Two‐way ANOVAs with Tukey post‐hoc tests were used to determine significance (α= 0.05).A significant interaction between LPS and SM‐I‐26 (p<0.0001) was found on mean nitrite. Within no LPS, mean nitrite was similar across all concentrations of SM‐I‐26. Within 10 ng/ml LPS, a trend was found with decreased nitrite with 10 and 1000 nM SM‐I‐26 compared to vehicle. Within 100 ng/ml LPS, both 10 and 1000 nM SM‐I‐26 significantly decreased nitrite compared to vehicle control (p<0.0001).Significant interactions were found between SM‐I‐26 and LPS on the mean ddcts of Tnf‐α (p<0.0001) and Il‐β, (p<0.0001). At 0 and 10 ng/mL LPS, 1000 nM SM‐I‐26 significantly increased the mean ddct of Tnf‐α compared to their vehicle controls (p<0.0001). Within 100 ng/ml LPS, SM‐I‐26 dose‐dependently increased the mean ddct for Tnf‐α (10 nM: p= 0.0067, 1000nM: p<0.0001, Tukey) compared to vehicle. These results indicate that 1000 nM SM‐I‐26 significantly decreased Tnf‐α mRNA expression under inflammatory conditions. For Il‐1β, the mean ddcts were similar across all concentrations of SM‐I‐26 with no LPS. At 100 ng/ml LPS, 10 nM and 1000 nM SM‐I‐26 significantly increased the mean ddcts for Il‐β (p<0.0001, and p=0.0040, respectively), indicating these concentrations of SM‐I‐26 decreased Il‐1β mRNA expression with inflammation. For Il‐6, LPS (p<0.0001) and SM‐I‐26 (p<0.0001), but not their interaction (p=0.1106) significantly impacted the mean ddct. SM‐I‐26 at 10 and 1000 nM significantly increased the mean ddct of Il‐6 compared to no SM‐I‐26 (p<0.0001 and p=0.0009, respectively), indicating that SM‐I‐26 decreased Il‐6 mRNA expression.These results show treatment with SM‐I‐26 significantly decreased Tnf‐α, Il‐6, and Il‐1β mRNA expression and mean nitrite levels with increasing LPS inflammatory stimulation. These results support the use of SSTR4 agonists for the mitigation of microglial activation, which could help in the treatment of AD progression.Support or Funding InformationThis work is supported by the National Institutes of Health, National Institute of Aging (R01AG047858)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
3,4,5-Trisubstituted-1,2,4-triazole somatostatin receptor-4 agonist SAR.
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