1 Recent studies have shown that sodium butyrate and other short-chain fatty acids (SCFAs) can prevent inflammation in colon diseases. Our aim was to elucidate whether sodium butyrate and SCFAs regulate the inflammatory responses in different neural inflammation models in cell cultures. 2 Inflammatory responses to LPS-induced microglial activation were recorded by the secretion of nitric oxide (NO) and cytokines IL-6 and TNF-a and related to the changes in the DNA-binding activities of NF-kB complex. 3 We observed that sodium butyrate is strongly anti-inflammatory against LPS-induced responses in rat primary microglia as well as in hippocampal slice cultures and in neural cocultures of microglial cells, astrocytes and cerebellar granule neurons. 4 In murine N9 microglial cell line, instead, sodium butyrate and other SCFAs (propionate, valerate and caproate) enhanced the LPS-induced inflammatory response. 5 The pretreatment with butyrate before LPS exposure induced an equal or more enhanced response than simultaneous exposure with butyrate and LPS. This indicates that butyrate induces an adaptative response against microglial activation. 6 We also observed that butyrate treatment both in transformed N9 cells and in hippocampal slice cultures downregulates the NF-kB-binding capacity induced by LPS stimulation. 7 Our results show that butyrate is anti-inflammatory in primary, brain-derived microglial cells, as observed recently in colon diseases, but proinflammatory in transformed, proliferating N9 microglial cells, which may be related to the anticancer properties of butyrate observed in tumor cells.
This review aims to cover experimental data on oxidative effects of low-intensity radiofrequency radiation (RFR) in living cells. Analysis of the currently available peer-reviewed scientific literature reveals molecular effects induced by low-intensity RFR in living cells; this includes significant activation of key pathways generating reactive oxygen species (ROS), activation of peroxidation, oxidative damage of DNA and changes in the activity of antioxidant enzymes. It indicates that among 100 currently available peer-reviewed studies dealing with oxidative effects of low-intensity RFR, in general, 93 confirmed that RFR induces oxidative effects in biological systems. A wide pathogenic potential of the induced ROS and their involvement in cell signaling pathways explains a range of biological/health effects of low-intensity RFR, which include both cancer and non-cancer pathologies. In conclusion, our analysis demonstrates that low-intensity RFR is an expressive oxidative agent for living cells with a high pathogenic potential and that the oxidative stress induced by RFR exposure should be recognized as one of the primary mechanisms of the biological activity of this kind of radiation.
Type 2 human sirtuin (SIRT2) is a NAD(+)-dependent cytoplasmic protein that is colocalized with HDAC6 on microtubules. SIRT2 has been shown to deacetylate alpha-tubulin and to control mitotic exit in the cell cycle. To date, some small molecular inhibitors of SIRT2 have been identified; however, more inhibitors are still needed to improve the understanding of SIRT2 biological function and to discover its possible therapeutic indications. In this paper, an in silico identification procedure is described for discovering novel SIRT2 inhibitors. Molecular modeling and virtual screening were utilized to find potential compounds, which were then subjected to experimental tests for their SIRT2 inhibitory activity. Five of the 15 compounds tested in vitro showed inhibitory activity toward SIRT2, yielding a hit ratio of 33% in a micromolar level and thus demonstrating the usefulness of this procedure in finding new bioactive compounds. Two of the five compounds yielded in vitro IC(50) values of 56.7 and 74.3 microM, and these can be considered as novel inhibitors of SIRT2. On the basis of our results, a phenol moiety on the active compound is suggested to be important for SIRT2 inhibitory activity. This phenol group, together with a hydrophobic moiety and hydrogen-bonding features, is suggested to form an active SIRT2 pharmacophore.
The activation of microglial cells is involved in the pathogenesis of a variety of neurodegenerative diseases, stroke and traumatic brain injuries. Recent studies suggest that protein acetylation can affect the extent of inflammatory responses. Our aim was to elucidate whether histone deacetylase inhibitors, inducers of protein hyperacetylation, regulate the inflammatory response in neural models of inflammation in vitro and whether neurone-glia interactions affect this regulation. Interestingly, we observed that histone deacetylase inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid, strongly potentiated the lipopolysaccharide (LPS)-induced inflammatory response in murine N9 and rat primary microglial cells as well in neural co-cultures and hippocampal slice cultures. TSA clearly potentiated the LPSinduced expression of interleukin (IL)-6 and inducible nitric oxide synthase mRNAs, as well as the secretion of cytokines IL-6, tumour necrosis factor-a and macrophage inflammatory protein (MIP)-2, and nitric oxide (NO). Co-culture and slice culture experiments showed that the presence of astrocytes and neurones did not stimulate or prevent the pro-inflammatory potentiation induced by histone deacetylase inhibitor in microglial cells. The potentiation of cytokine and NO responses was blocked by the nuclear factor kappa B (NF-jB) inhibitors caffeic acid phenethyl ester and helenalin, demonstrating that the NF-jB signalling pathway is involved. The DNA-binding activity of the NF-jB complex was strongly increased by LPS treatment but not enhanced by TSA. This suggests that potentiation of the inflammatory response is not dependent on the level of cytoplasmic NF-jB activation or DNA-binding activity but that site of action may be at the level of transcriptional regulation. Our results suggest that environmental stresses, ageing, diet and diseases that regulate protein acetylation status may also affect the inflammatory response. Keywords: acetylation, Alzheimer, epigenetics, histone deacetylase, neurodegeneration, nuclear factor kappa B. Abbreviations used: CAPE, caffeic acid phenethyl ester; FBS, fetal bovine serum; HDAC, histone deacetylase; IL, interleukin; iNOS, inducible nitric oxide synthase; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; M344, 4-dimethylamino-N-(6-hydroxycarbamoylhexyl)-benzamide; MIP, macrophage inflammatory protein; NF-jB, nuclear factor kappa B; NO, nitric oxide; SAHA, suberoylanilide hydroxamic acid; SDS, sodium dodecyl sulfate; TNF, tumour necrosis factor; TSA, trichostatin A.
Changes occur in gene expression during aging in vivo and in replicative senescence in vitro, suggesting that aging can affect gene regulation. We have recently observed age-related changes in ubiquitously expressed, oxidative stress-responsive nuclear factor-kappa B (NF-kappa B) pathway during aging. Here we report a significant age-related increase in nuclear NF-kappa B binding activity together with increased protein levels of p52 and p65 components in rat liver. An additional, higher molecular weight protein band seen in their western blots suggests that their post-translational modification (but not phosphorylation) occurs in liver, which might affect their nuclear localization and binding activity during aging. However, aging did not affect the protein levels of the main I kappa B inhibitors (I kappa B alpha and I kappa B beta) or I kappa B kinase (IKK)-complex subunits (IKK alpha, -beta, and -gamma) involved in NF-kappa B activation. In addition, the level of Ser32-phosphorylated I kappa B alpha was unaffected by age, suggesting that neither the IKK complex nor altered level of the main inhibitors is involved in the observed up-regulation of NF-kappa B binding activity. Furthermore, the expression of NF-kappa B mRNAs (p50, p52, p65, and c-rel) and the mRNAs of their inhibitors (I kappa B alpha and I kappa B beta) did not show any statistically significant age-related changes. These results indicate that the expression level of NF-kappa B genes is not significantly affected by aging. The up-regulation of constitutive nuclear NF-kappa B binding activity and increased levels of nuclear p52 and p65 proteins might affect the expression of some NF-kappa B target genes in the aging liver.
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