Individuals with type 2 diabetes (T2D) display vascular insulin resistance and decreased nitric oxide production leading to vasoconstriction and atherosclerosis. Soluble factors such as pro-inflammatory molecules, and various genetic and epigenetic mechanisms have been implicated to induce insulin resistance in vascular endothelial cells. Epigenetic mechanisms such as altered promoter DNA methylation have been demonstrated in development and progression of metabolic disorders and atherosclerosis. However, underlying precise epigenetic mechanisms regulating cross talk between insulin signaling genes and inflammation in vascular cells remains to be fully understood. Human endothelial cells when (a) treated with interleukin-6 (IL-6) and insulin together, (b) pretreated with IL-6, and (c) under hyperinsulinemic conditions led to a state of vascular insulin resistance resulting in decreased Akt/eNOS activation and subsequent stabilization of STAT3 phosphorylation. IL-6 abrogated insulin effects on angiogenesis in 3D spheroid and matrigel assays. IL-6-induced insulin resistance was associated with decreased activity of DNA methyltransferase isoforms and global DNA hypomethylation, which inversely correlated with S-phase of cell cycle. CpG microarray analysis in IL-6 treated endothelial cells revealed promoters associated hypo- and hypermethylation of 199 and 98 genes respectively. Promoter DNA methylation status of genes associated with insulin signaling and angiogenesis such as RPS6KA2, PIK3R2, FOXD3, EXOC7, MAP3K8, ITPKB, EPHA6, IGF1R, and FOXC2 were validated by bisulfite DNA sequencing. Concentration and time-dependent analysis revealed that IL-6 reduced DNMT1 and DNMT3B but not DNMT3A protein levels. Our data indicate a causal link between IL-6-induced changes in global and promoter-specific DNA methylation, due to reduced DNMT1 and DNMT3B protein levels leading to altered expression of critical genes involved in insulin signaling and angiogenesis.
Coleus aromaticus (Benth, Family: Laminaceae), Indian Oregano native to India and Mediterranean, is well known for its medicinal properties. A preliminary study was undertaken to elucidate in vitro free radical scavenging potential and inhibition of lipid peroxidation by C.aromaticus hydroalcoholic extract (CAE). Anti-clastogenic and radioprotective potential of CAE were studied using micronucleus assay after irradiating Chinese hamster fibroblast (V79) cells. CAE at 10, 20, 40, 60, 80, 100 and 120 mug/ml resulted in a dose-dependent increase in radical scavenging ability against various free radicals viz., 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), superoxide anion (O(2)(*-)), hydroxyl (OH(*)) and nitric oxide (NO(*)) generated in vitro. A maximum scavenging potential was noticed at 100 mug/ml and a saturation point was reached thereafter with the increasing doses of CAE. The free radical scavenging potential of the extract was in the order of DPPH > ABTS > Superoxide > Hydroxyl > Nitric oxide. CAE also exhibited a moderate inhibition of lipid peroxidation in vitro, with a maximum inhibition at 60 mug/ml (33%), attaining saturation at higher doses. The extract also rendered protection against radiation induced DNA damage, as evidenced by the significant (P < 0.05) decrease in the percentage of radiation-induced micronucleated cells (MN) and frequency of micronuclei (total). A maximum anticlastogneic effect/ radioprotection was noticed at a very low concentration i.e., 5 mug/ml of CAE, treated 1 h prior to 2 Gy of gamma radiation. A significant (P < 0.0001) anticlastogenic/radioprotective effect was also observed when the cells were treated with an optimum dose of CAE (5 mug/ml) 1 h prior to 0.5, 1, 2 and 4 Gy of gamma radiation compared with the respective radiation control groups. Overall, our results established an efficient antioxidant, anticlastogenic and radioprotective potential of CAE, which may be of great pharmacological importance.
Background:Human variations related to immune response and disease susceptibility is well-documented in Ayurveda. Prakriti (body constitution) is the basic constitution of an individual established at the time of birth and distinguishes variations, into three broad phenotype categories such as vata, pitta and kapha. Variation in immune response is often attributed to and measured from the difference in cluster differentiation (CD) markers expressed in lymphocytes. Currently, there are no reports available on the expression of CD markers related to prakriti.Objective:This is a pilot study performed to evaluate a panel of lymphocyte subset CD markers in dominant prakriti individuals.Materials and Methods:Immunophenotyping was carried out using whole blood from a total of healthy 222 subjects, who are grouped into kapha (n = 95), pitta (n = 57) and vata (n = 70) prakritis. CD markers such as CD3, CD4, CD8, CD14, CD25, CD56, CD69, CD71 and HLA-DR were analyzed using flow cytometry method. Differences between groups were analyzed using one-way ANOVA or Kruskal-Wallis analysis of variance (ANOVA) and multiple comparisons between groups were performed by Bonferroni or Mann-Whitney U test with corrections for type I error respectively. Significance was evaluated by ANOVA and Pearson's correlation.Results:We observed a significant difference (P < 0.05) in the expression of CD markers such as CD14 (monocytes), CD25 (activated B cells) and CD56 (Natural killer cells) between different prakriti groups. CD25 and CD56 expression was significantly higher in kapha prakriti samples than other prakriti groups. Similarly, slightly higher levels of CD14 were observed in pitta prakriti samples.Conclusion:Significant difference in the expression of CD14, CD25 and CD56 markers between three different prakriti is demonstrated. The increased level of CD25 and CD56 in kapha prakriti may indicate ability to elicit better immune response, which is in conformity with textual references in Ayurveda.
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