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Aim: In Japan, goreisan (GRS) is used to alleviate cerebral edema and relieve headaches. Although improvement of water maldistribution in the brain may be one of the mechanisms of action of GRS for cerebral edema and headache, scientific evidence is limited. Here, we aimed to investigate the action mechanism of GRS against cerebral edema and headaches, focusing on water dynamics in the brain. Methods: We used a well‐established mouse model of cerebral edema to evaluate the effects of GRS on related symptoms and brain water content. The mouse model was subjected to magnetic resonance imaging (MRI) using H217O to assess water dynamics in the brain. The effect of GRS on water permeability through aquaporin‐4 (AQP4) was also examined in vitro. Results: GRS inhibited the loss of righting reflex and improved survival in the mouse model by ameliorating the increase in brain water content. The MRI evaluation of water dynamics suggested that GRS inhibited water influx into the brain. Evaluation of water permeability via AQP4 in Xenopus laevis oocytes and HEK293 cells showed that GRS inhibited AQP4 function. Conclusion: GRS suppressed the ubiquity of water in the brain in a mouse model of cerebral edema, suggesting inhibition of AQP4 function (not AQP4 expression) as one of the action mechanisms of GRS. Our findings provide fundamental evidence for the clinical efficacy of GRS against cerebral edema and headaches. [ABSTRACT FROM AUTHOR]

The current study was conducted to elucidate the mechanism through which TNF-[alpha] stimulates expression of MUC 1, a membrane-tethered mucin. A549 human lung alveolar cells treated with TNF-[alpha] exhibited significantly higher MUC 1 protein levels in detergent lysates compared with cells treated with vehicle alone. Increased MUC1 protein levels were correlated with significantly higher levels of MUC1 mRNA in TNF-[alpha]-treated cells compared with controls. However, TNF-[alpha] did not alter MUC1 transcript stability, implying increased de novo transcription induced by the cytokine. TNF-[alpha] increased MUC1 gene promoter activity in A549 cells transfected with a promoter-luciferase reporter plasmid. Both U0126, an inhibitor of MEK1/2, and dominant negative ERK1 prevented TNF-[alpha]-induced MUC1 promoter activation, and antiTNFR1 antibody blocked TNF-[alpha]-stimulated ERK1/2 activation. MUC1 promoter activation by TNF-[alpha] also was blocked by mithramycin A, an inhibitor of Sp1, as well as either deletion or mutation of a putative Spl binding site in the MUC1 promoter located between nucleotides -99 and -90. TNF-[alpha]-stimulated binding of Sp1 to the MUC1 promoter in intact cells was demonstrated by chromatin immunoprecipitation assay. We conclude that TNF-[alpha] induces MUC1 gene transcription through a TNFR1 [right arrow] MEK1/2 [right arrow] ERK1 [right arrow] Sp1 pathway. tumor necrosis factor-[alpha]; Spl; mitogen-activated protein kinase

In this study, we investigated the regulation and mechanism of IL-8 expression by A549 human lung carcinoma cells treated with neutrophil elastase (NE). NE-treated cells exhibited significantly higher IL-8 protein levels in culture media compared with cells treated with vehicle alone. Blocking of gene transcription with actinomycin D suggested that NE stimulated IL-8 synthesis via increased mRNA expression, which was verified by real-time RT-PCR. NE activated the IL-8 promoter but did not alter the stability of its mRNA, confirming that the protease induced IL-8 synthesis through increased gene transcription. The results from the use of chemical inhibitors and mutant gene constructs against various signal transduction components seem to suggest the linear signaling pathway involving the activation of PKC-[delta] [right arrow] dual oxidase 1 [right arrow] reactive oxygen species [right arrow] TNF-[alpha]-converting enzyme [right arrow] EGF receptor [right arrow] p38 [right arrow] NF-[kappa]B for NE-activated IL-8 gene expression. A NF-[kappa]B potential binding site, located between nucleotides -82 and -69 of the IL-8 promoter, was identified as necessary for NE-induced IL-8 transcription. We conclude that NE increases IL-8 transcription through p38/NF-[kappa]B activation via EGFR transactivation. protease; signal; airway; epithelial; epidermal growth factor receptor doi:10.1152/ajplung.00471.2004

We previously reported MUCI was a cell surface receptor for Pseudomonas aeruginosa, and binding of bacteria to cells was significantly reduced by pretreatment with neutrophil elastase (NE) (Lillehoj EP, Hyun SW, Kim BT, Zhang XG, Lee DI, Rowland S, and Kim KC. Am J Physiol Lung Cell Mol Physiol 280: L181-L187, 2001). The current study was conducted to ascertain NE effects on MUC1 gene transcription, and MUC1 protein synthesis and degradation. A549 human lung carcinoma cells treated with NE exhibited significantly higher MUC 1 protein levels in detergent lysates compared with cells treated with vehicle alone. Also, MUC1 protein shed into cell-conditioned medium was rapidly and completely degraded by NE. Actinomycin D blocked NE-stimulated increase in MUC1 protein expression, suggesting a mechanism of increased gene transcription that was confirmed by measurement of quantitatively greater MUC1 mRNA levels in NE-treated ceils compared with controls. However, NE did not alter MUC1 mRNA stability, implying increased de novo transcription induced by the protease. NE increased promoter activity in A549 cells transfected with MUC1 gene promoter-luciferase reporter plasmid. This effect of NE was completely blocked by mithramycin A, an inhibitor of Sp1, as well as mutation of one of the putative Spl binding sites in MUC1 promoter located at -99/-90 relative to transcription initiation site. EMSA revealed NE enhanced binding of Spl to this 10-bp segment in a time-dependent manner. These results indicate the increase in MUC1 gene transcription by NE is mediated through increase in Spl binding to -99/-90 segment of MUC1 promoter. mucin; transcription; protease; epithelial; mithramycin A

Eosinophils are known to play a vital role in allergic conditions such as asthma. Their action is linked to the release of cytotoxic proteins and other mediators that trigger hyperreactivity in respiratory muscle cells. Eosinophils have also been shown to increase phosphatidylcholine (PC) secretion in primary cultures of rat type II pneumocytes. Further examination of the role of eosinophil major basic protein (MBP) shows that MBP induces PC secretion and provides mechanical stability in rat type II pneumocytes, thereby helping to protect against lung atelectasis.

Asthma is a pulmonary inflammation characterized by the excessive production of airway mucus. So far, the treatment of asthma has been limited to glucocorticoids. Herein, human pulmonary mucoepidermoid carcinoma cells were examined after dexamethasone treatment. The cells showed an increase in mRNA levels of two human mucin genes, MUC-2 and MUC-5AC. They also produced low levels of high-molecular-weight glycoconjugates. These results indicate that dexamethasone may be an effective approach for managing inflammation in asthma.