No abstract

Traditional medicine has been a fertile source for revealing novel lead molecules for modern drug discovery. In plants, terpenoids represent a chemical defense against environmental stress and provide a repair mechanism for wounds and injuries. Interestingly, effective ingredients in several plant-derived medicinal extracts are also terpenoid compounds of monoterpenoid, sesquiterpenoid, diterpenoid, triterpenoid and carotenoid groups. Inflammatory diseases and cancer are typical therapeutic indications of traditional medicines. Thus folk medicine supports the studies which have demonstrated that plant-derived terpenoid ingredients can suppress nuclear factor-kappaB (NF-kappaB) signaling, the major regulator in the pathogenesis of inflammatory diseases and cancer.We review the extensive literature on the different types of terpenoid molecules, totalling 43, which have been verified both inhibiting the NF-kappaB signaling and suppressing the process of inflammation and cancer. It seems that during evolution, plants have established a terpene-based host defense which also represents a cornucopia of effective therapeutic compounds for common human diseases.

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.

n 1a-f (n = 1-6) 2a-d (n = 2, 4, 8, 16) n n 3a-e (n = 1-6) 4a-e (n = 1-4) n 5330 5335 5340 5345 5350 5355 5360 5365 m / z

No abstract

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.

Homo- and heterodivalent crown-ammonium pseudorotaxanes with different spacers connecting the two axle ammonium binding sites have been synthesized and characterized by NMR spectroscopy and ESI mass spectrometry. The homodivalent pseudorotaxanes are investigated with respect to the thermodynamics of divalent binding and to chelate cooperativity. The shortest spacer exhibits a chelate cooperativity much stronger than that of the longer spacers. On the basis of crystal structure, this can be explained by a noninnocent spacer, which contributes to the binding strength in addition to the two binding sites. Already very subtle changes in the spacer length, i.e., the introduction of an additional methylene group, cause substantial changes in the magnitude of cooperative binding as expressed in the large differences in effective molarity. With a similar series of heterodivalent pseudorotaxanes, the spacer effects on the barrier for the intramolecular threading step has been examined with the result that the shortest spacer causes a strained transition structure and thus the second binding event occurs slower than that of the longer spacers. The activation enthalpies and entropies show clear trends. While the longer spacers reduce the enthalpic strain that is present in the transition state for the shortest member of the series, the longer spacers become entropically slightly more unfavorable because of conformational fixation of the spacer chain during the second binding event. These results clearly show the noninnocent spacers to complicate the analysis of multivalent binding. An approximate description which considers the binding sites to be connected just by a flexible chain turns out to be more a rough approximation than a good model. The second conclusion from the results presented here is that multivalency is expressed in both the thermodynamics and the kinetics in different ways. A spacer optimized for strong binding is suboptimal for fast pseudorotaxane formation.

Research on aging in model organisms has revealed different molecular mechanisms involved in the regulation of the lifespan. Studies on Saccharomyces cerevisiae have highlighted the role of the Sir2 family of genes, human Sirtuin homologs, as the longevity factors. In Caenorhabditis elegans, the daf-16 gene, a mammalian homolog of FoxO genes, was shown to function as a longevity gene. A wide array of studies has provided evidence for a role of the activation of innate immunity during aging process in mammals. This process has been called inflamm-aging. The master regulator of innate immunity is the NF-kappaB system. In this review, we focus on the several interactions of aging-associated signaling cascades regulated either by Sirtuins and FoxOs or NF-kappaB signaling pathways. We provide evidence that signaling via the longevity factors of FoxOs and SIRT1 can inhibit NF-kappaB signaling and simultaneously protect against inflamm-aging process.