Our results indicate that EMD induces the formation of osteoclasts through interaction with RANKL, while ERK and p38 MAPK may play a critical role in the enhancement of osteoclast formation in RAW 264.7 cells.
Myeloperoxidase (MPO)-generated halogenating molecules, such as hypochlorous acid and hypobromous acid (HOBr), in inflammatory regions are postulated to contribute to disease progression. In this study, we showed that ergothioneine (EGT), derived from an edible mushroom, inhibited MPO activity as well as the formation of 8-bromo-2'-deoxyguanosine in vitro. The HOBr scavenging effect of EGT is higher than those of ascorbic acid and glutathione. We initially observed that the administration of Coprinus comatus, an edible mushroom containing a high amount of EGT, inhibited the UV-B-induced inflammatory responses and DNA halogenation, suggesting that EGT is a promising anti-inflammatory agent from mushrooms.
Abstract. Although gemcitabine (GEM) is frequently used in the treatment of pancreatic cancer, the effects are limited. To increase the inhibitory effect of GEM, the identification of a molecular target is needed. Recent studies have revealed that doublecortin-like kinase 1 (Dclk1) positively regulates tumor growth, invasion, metastasis, factors related to epithelialmesenchymal transition (EMT), pluripotency, angiogenesis, and anti-apoptosis in pancreatic cancer cells. Therefore, Dclk1 is a potential therapeutic target for pancreatic cancer. However, the Dclk1-signaling pathway including its substrate proteins remains to be elucidated. To identify the candidate substrate proteins phosphorylated by Dclk1, we performed a cancer-related phosphorylated protein microarray using Dclk1-inhibited MIA Paca2 cells. Expression levels of phosphorylated cdc25A (p-cdc25A) and phosphorylated Chk1 (p-Chk1), belonging to the ATR pathway, were decreased by treatment with Dclk1 inhibitor LRRK2-IN-1 (LRRK), indicating Dclk1 involvement in the ATR pathway. Consistent with this finding, the GEM-induced p-Chk1 expression was significantly decreased by treatment with LRRK. Notably, combined treatment with GEM and LRRK allowed cell cycle progression without arresting at S phase, while individual treatment with GEM induced cell cycle arrest at S phase. In addition, combined treatment with GEM and LRRK increased the number of γ-H2AX-positive cells compared with that upon individual treatments. Moreover, LRRK alone, and combined treatment with GEM and LRRK, induced caspase-3 activation and PARP1 cleavage, in contrast to treatment with GEM alone. Finally, combined treatment with GEM and LRRK significantly reduced cell survival compared to individual treatment with GEM. These results indicate that Dclk1 inhibition in combination with GEM treatment offers a novel approach to treat pancreatic cancer cells.
is frequently used in colorectal cancer treatment, but with limited success. The aim of the present study was to explore the cytotoxic effects of 5-FU, in combination with inhibition of doublecortin-like kinase 1 (Dclk1), a tumor stem cell marker that regulates pro-survival signaling in colorectal cancer cells, in the human colon cancer cell line, The effects of 5-FU treatment plus Dclk1 inhibition on the phosphorylation of checkpoint kinase 1 (Chk1), cell cycle, DNA damage, apoptosis, and cell survival in COLO-320 cells were evaluated. Results: Combined treatment with 5-FU and a Dclk1 inhibitor, LRRK2-IN-1 (LRRK), decreased 5-FU-induced phosphorylation of Chk1 and canceled 5-FU-induced cell-cycle arrest at the S phase. Combined treatment with 5-FU and LRRK failed to induce poly (ADP-ribose) polymerase 1 (PARP-1) cleavage, but tended to decrease cell survival compared to individual treatment with 5-FU or LRRK. Conclusion: These results indicate that a combination of 5-FU and LRRK may be an effective, novel approach for colorectal cancer therapy.Colorectal cancer is the third leading cause of cancer-related death in the world and represents a severe threat to human health (1). 5-Fluorouracil (5-FU), a pyrimidine analogue, induces the inhibition of DNA synthesis through inhibition of thymidylate synthetase and is misincorporated into DNA and RNA, leading to the induction of cell-cycle arrest at G 1 /S phase (2). Presently, the combination of infused 5-FU/leucovorin (LV) plus irinotecan or oxaliplatin, known as the FOLFIRI (3) and FOLFOX4 regimens (4), represents the standard first-line chemotherapy. However, the emergence of tumor cells with acquired pharmacological resistance to these agents limits the antitumor effect of these therapies. Tumor cell-acquired pharmacological resistance leads to development of metastasis, which is responsible for approximately 90% of colorectal cancer-related mortality (5).5-FU treatment induces the phosphorylation of checkpoint kinase 1 (Chk1), a cell-cycle checkpoint protein, and arrests cell-cycle progression at the S phase (6, 7). Thus, combined treatment with 5-FU and Chk1 inhibition is expected to increase cell death due to lethal chromosomal instability caused by the progression of the cell cycle without repairing the damaged DNA at the arrested S phase. Therefore, the combined effect of 5-FU and Chk1 inhibition has previously been examined. As expected, Chk1 inhibition sensitized the cells to 5-FU-induced cytotoxicity (6-8). Furthermore, this combined treatment is found to increase cell death in colorectal cancer cells compared to individual treatment with 5-FU or Chk1 inhibitor (9). However, Chk1 plays an important role in the cell-cycle checkpoint of normal cells, and therefore combined treatment with 5-FU and Chk1 inhibitor may lead to severe side-effects caused by cytotoxicity in normal cells. Therefore, it is necessary to identify a molecular target specifically in cancer cells to increase the cytotoxic effect of 5-FU without causing severe side-effects.Doublecortin-l...
We measured the anti-oxidative and anti-inflammatory activities of hot water extracts prepared from 11 species of mushrooms. Anti-oxidative activity was evaluated using the oxygen radical absorbance capacity method, and anti-inflammatory activity was examined by measuring the inhibition of lysine chloramine formation by hypochlorous acid. Hot water extracts of Grifola gargal (G. gargal) showed the strongest anti-oxidative activity and inhibitory effects on lysine chloramines. Hot water extracts of G. gargal were evaluated by HPLC and divided into 8 fractions. The most active fraction among these 8 fractions was further purified by preparative HPLC. The active component isolated by HPLC was identified as ergothioneine (EGT) using spectral analysis. On HPLC analysis, the EGT content in G. gargal was the highest among the 11 species of mushrooms. We also examined the protective role of EGT by examining the inflammatory response of adipocyte cells induced by tumor necrosis factor-α.
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