It has not been determined yet whether the ERK-MAPK pathway regulates longevity of metazoans. Here, we show that the Caenorhabditis elegans ERK cascade promotes longevity through the two longevity-promoting transcription factors, SKN-1 and DAF-16. We find that RNAi of three genes, which constitute the ERK cascade (lin-45/RAF1, mek-2/MEK1/2, and mpk-1/ERK1/2), results in reduction of life span. Moreover, RNAi of lip-1, the gene encoding a MAPK phosphatase that inactivates MPK-1, increases life span. Epistasis analyses show that the ERK (MPK-1) cascade-mediated life span extension requires SKN-1, whose function is mediated, at least partly, through DAF-2/DAF-16 insulin-like signaling. MPK-1 phosphorylates SKN-1 on the key sites that are required for SKN-1 nuclear accumulation. Our results also show that one mechanism by which SKN-1 regulates insulin-like signaling is through the regulation of expression of insulin-like peptides. Our findings thus identify a novel ERK-MAPK-mediated signaling pathway that promotes longevity.Recent genetic studies in a variety of model organisms are beginning to reveal the signal transduction networks capable of regulating life span. The insulin-like signaling pathway plays a central role in these networks. In Caenorhabditis elegans, the FOXO transcription factor DAF-16 is required for life span extension by a mutation in daf-2, the insulin-like receptor (1-3). Recently, the longevity-promoting transcription factor SKN-1 has been shown to be inhibited by the insulin-like signaling pathway (4). However, it has not been fully elucidated how the insulin-like signaling pathway interacts with the other distinct signaling pathways to regulate longevity.The ERK-MAPK cascades are evolutionarily conserved signaling modules in eukaryotic cells and transduce signals from the cell surface to the nucleus. These cascades control diverse cellular processes, such as cell proliferation and differentiation (5-8). It has also been demonstrated that increasing nuclear ERK activity can extend replicative life span of diploid human cells (9). Furthermore, a recent report has shown that the increase in life span in mice lacking type 5 adenylyl cyclase correlates with increased ERK-MAPK signaling and that overexpression of mammalian ERK2 increases the chronological life span of yeast (10). However, it has not been determined yet whether the ERK-MAPK cascade promotes longevity of metazoans. In addition, molecular mechanisms by which ERK signaling regulates longevity have remained unclear. Here, we show that the ERK (MPK-1) cascade functions to extend life span in C. elegans. Our analyses show that ERK signaling acts through SKN-1 to regulate the DAF-2/DAF-16 insulin-like signaling and that MPK-1 phosphorylates SKN-1 on the key sites that are required for SKN-1 nuclear accumulation. Moreover, our data suggest that SKN-1 is involved in the regulation of life span through repression of expression of insulin-like peptides. Thus, our results demonstrate a role of the ERK signaling pathway in extending longevity a...
Licorice (Glycyrrhizae radix) is the roots and stolons of Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra Linnaeus in the Japanese Pharmacopoeia. Glycyrrhizae radix has been widely used as a sweetener and a traditional medicine. A Glycyrrhizae radix extract contains many constituents and has antispasmodic, antitussive, anti-ulcer, and anti-inflammatory effects. However, reports comparing the anti-inflammatory effects of these constituents are very few. Here, we purified several constituents from the roots and stolons of G. uralensis and examined and compared their anti-inflammatory effects by monitoring the levels of the inflammatory mediator, nitric oxide (NO), in interleukin (IL)-1β-treated rat hepatocytes. From the G. uralensis extract, we purified the main constituent glycyrrhizin and the constituents that are characteristic of G. uralensis (chalcones and flavanones). These constituents suppressed NO production in IL-1β-treated rat hepatocytes, and isoliquiritigenin showed the greatest suppression activity. Isoliquiritigenin, isoliquiritin, and liquiritigenin significantly decreased both protein and mRNA for the inducible nitric oxide synthase. These constituents reduced the levels of mRNAs encoding tumor necrosis factor α and IL-6. In contrast, although glycyrrhizin is abundant, it showed a 100-fold lower potency in NO suppression. Therefore, both glycyrrhizin and the minor constituents (isoliquiritigenin, isoliquiritin, and liquiritigenin) may be responsible for the anti-inflammatory effects of G. uralensis. It is also implied that these constituents may have a therapeutic potential for inflammatory hepatic disorders.
Phellodendri Cortex (Obaku in Japanese) and Coptidis Rhizoma (Oren), both of which contain berberine, have been used to prepare the kampo formula orengedokuto to treat inflammatory diseases, including dermatitis, gastric ulcers, and gastritis. These drugs are blended differently in other formulas, such as the use of Phellodendri Cortex in shichimotsukokato to treat hypertension and Coptidis Rhizoma in hangeshashinto to treat diarrhea and stomatitis. However, the differences in their medicinal properties are not well characterized. We prepared extracts from Phellodendron amurense bark (PAB) and Coptis chinensis rhizome (CCR) and separated them into alkaloid and non-alkaloid fractions. Anti-inflammatory effects were examined by monitoring the production of nitric oxide (NO), which is a pro-inflammatory mediator. A non-alkaloid fraction of the PAB extract suppressed NO production in hepatocytes more efficiently than that of the CCR extract. When each non-alkaloid fraction of the PAB and CCR extracts was administered to mice, the fractions of both extracts decreased the levels of mRNAs encoding inducible NO synthase and molecules in the interleukin-1β signaling pathway. Limonin and obakunone identified in the PAB non-alkaloid fraction suppressed NO production, exhibiting IC values of 16 and 2.6 μM, respectively, whereas berberine and coptisine displayed IC values of 12 and 14 μM, respectively. Limonin and obakunone reduced the expression of the iNOS gene, probably through the transcription factor nuclear factor-κB. Therefore, both limonoids and alkaloids may be responsible for the anti-inflammatory effects of the PAB extract, whereas alkaloids may be primarily responsible for those of the CCR extract. The different composition of the constituents may modulate the anti-inflammatory effects of Phellodendri Cortex and Coptidis Rhizoma.
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