Eriobotrya japonica leaf is a traditional herbal medicine that contains numerous triterpenes, which have various pharmacological properties. In this study, we investigated the anti-proliferative activity of four triterpenes derived from E. japonica, including corosolic acid (CA), ursolic acid (UA), maslinic acid (MA) and oleanolic acid (OA), in human leukemia cell lines. CA showed the strongest anti-proliferative activity in all of the leukemia cell lines tested, but not in normal human skin fibroblast cell lines. To determine the mechanism underlying the anti-proliferative effect of CA, we examined the effect of CA on molecular events known as apoptosis induction. CA induced chromatin condensation, DNA fragmentation, sub-G1 phase DNA, activation of caspase-3, -8 and -9 and the cleavage of PARP in HL-60. CA also activated Bid and Bax, leading to the loss of mitochondrial membrane potential (Δψm) and cytochrome c release into the cytosol, whereas Bcl-2 and Bcl-xL were unaffected by CA. These results suggest that CA has an anti-proliferative effect on leukemia cells via the induction of apoptosis mediated by mitochondrial dysfunction and caspase activation. CA may be a potential chemotherapeutic agent for the treatment of human leukemia.
Eriobotryae folium (EF), the dried leaves of Eriobotrya japonica (Thunb.) Lindl. has been traditionally used to treat various diseases such as chronic bronchitis, cough, inflammation, skin diseases, and diabetes. In this study, we examined the effects of Eriobotryae folium extract (EFE) on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and prostaglandin E2(PGE2) in RAW264 murine macrophage cells. EFE suppressed LPS-induced NO and PGE2 production in a dose-dependent manner. Consistent with these observations, EFE reduced the LPS-induced expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at both protein and mRNA levels. Furthermore, EFE significantly inhibited LPS-induced NF-kappaB binding activity, which was associated with the inhibition of IkappaB-alpha degradation. EFE also attenuated LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK). These results suggest that the anti-inflammatory properties of EF might result from inhibition of iNOS and COX-2 expression through the downregulation of NF-kappaB activation and MAPK phosphorylation in LPS-stimulated RAW264 cells.
Paclitaxel-induced painful peripheral neuropathy is a major doselimiting factor. Recently, it has been reported that macrophages accumulated in the dorsal root ganglion of paclitaxel-treated rats, and their activation is suggested to contribute to generation and development of the neuropathy. However, the mechanism for macrophage activation is still unknown. In this study, to explore candidate genes involved in the mechanism for macrophage activation in the dorsal root ganglion of paclitaxel-treated rats, we developed model rats for paclitaxel-induced neuropathic pain and performed a microarray assay to analyze the changes of gene expressions in the dorsal root ganglion. Among the genes with changed expression levels, we focused on matrix metalloproteinase-3 (MMP-3, stromelysin-1) and CD163, a macrophage marker. By reverse transcription-polymerase chain reaction, the expression levels of MMP-3 and CD163 were markedly up-regulated in paclitaxel-treated dorsal root ganglion. As a result of immunohistochemical study, large ganglion neurons, but neither Schwann cells nor macrophages, predominantly expressed MMP-3. This MMP-3 up-regulation occurred prior to macrophage accumulation in the dorsal root ganglion. In addition, recombinant MMP-3 led to the activation of RAW264 macrophages in vitro. Taken together, the up-regulation of MMP-3 and following macrophage activation caused in the dorsal root ganglion might be a significant event to trigger a series of reactions developing paclitaxel-induced peripheral neuropathic pain. (Cancer Sci 2008; 99: 1618-1625) P aclitaxel is an antineoplastic agent used clinically to treat nonsmall-cell lung cancer and ovarian cancer.(1,2) Paclitaxel suppresses microtubule dynamics, causing mitotic arrest in dividing cells.(3) On the other hand, painful peripheral neuropathy is a major dose-limiting factor in clinical cancer chemotherapy with paclitaxel. (4,5) Although the administration of glutamine and acetyl-L-carnitine has been reported to relieve paclitaxel-induced neuropathic pain as symptomatic treatment, (6,7) its effectiveness shows large interindividual variation. To develop a specific treatment, the molecular mechanisms underlying paclitaxelinduced neuropathy should be explored.It has been assumed that paclitaxel-induced neuropathy is generally due to effects on axonal microtubules.(8) Paclitaxelinduced neuropathy is characterized by an ascending distal paresthesia and dysesthesia in a 'glove and stocking' distribution. (5,8) Blocking of axonal transport due to paclitaxel-induced disruption of microtubule dynamics, which seems to be a reasonable mechanism, has been observed in vitro.(9) Nerve biopsies from patients with taxane-induced neuropathy have shown evidence of a loss of large diameter afferents.(10) In contrast, it has been reported that administration of low dose of paclitaxel caused neuropathic pain without any change of axonal morphology. (11) Additively, in vitro, axonal transport was not impaired in DRG neurons exposed to paclitaxel at chemotherapeutic doses. (12) ...
Ghrelin, a gastric hormone, is a growth hormone-releasing peptide. Its serine-3 acylation with octanoic acid is essential for its orexigenic activity, and therefore, inhibition of the acylation of ghrelin may help in decreasing appetite and preventing obesity. This study aimed to establish a human gastric cell-based assay system to evaluate candidate inhibitors of octanoylated ghrelin production. In human gastric carcinoma AGS cells, obligatory factors for the posttranslational modification of ghrelin, such as certain prohormone convertases responsible for processing of proghrelin to the mature ghrelin and the enzyme-catalyzing acyl-modification of ghrelin, were well expressed, but ghrelin was expressed at low levels. Accordingly, we transfected a ghrelin-expressing vector into AGS cells and isolated a stable ghrelin-expressing cell line (AGS-GHRL8). AGS-GHRL8 cells secreted octanoylated ghrelin in accordance with the concentrations of octanoic acid in the culture medium. Given that ingested heptanoic acid is used for the acyl-modification of ghrelin, we evaluated whether heptanoic acid inhibits production of octanoylated ghrelin in AGS-GHRL8 cells. Butyric acid was used as a control. Indeed, heptanoic acid predictably decreased the secretion of octanoylated ghrelin, whereas butyric acid did not. The AGS-GHRL8 line established in this study will facilitate the screening of inhibitors of octanoylated ghrelin production. Keywords AGS cells, butyric acid, des-acyl ghrelin, heptanoic acid, octanoylated ghrelin 1036 Journal of Biomolecular Screening 18(9)Ingested medium-chain fatty acids are directly used for the acylation of ghrelin.13 Therefore, inhibition of ghrelin octanoylation may suppress hyperphagia and thus contribute to the prevention and improvement of obesity. The enzyme that catalyzes acyl-modification of ghrelin is ghrelin O-acyltransferase (GOAT), 14,15 also known as membrane-bound O-acyltransferase 4. It has also been reported that a few synthetic peptides can inhibit GOAT activity 16,17 ; these peptides may therefore be useful for preventing the production of octanoylated ghrelin. However, considering that peptidic compounds generally have poor oral bioavailability, nonpeptidic inhibitors of octanoylated ghrelin production for the prevention of hyperphagia and obesity are currently being explored.To investigate the inhibitors of ghrelin activation, an in vitro system for the evaluation of octanoylated ghrelin production would be useful. A number of assay systems to determine ghrelin levels and GOAT activity have been developed. 18 As a cell-based assay system, Sf9 insect cells infected with a recombinant baculovirus encoding mouse GOAT and GOAT/proghrelin-transfected HeLa cells have been used for the evaluation of peptidic inhibitors of ghrelin-octanoylation. 16,17 Moreover, systems using gastric cells are considered useful for the evaluation of octanoylated ghrelin production because ghrelin is principally produced in the gastric cells and GOAT is largely restricted to the stomach.14,15 Howe...
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