Aging is a major risk factor of osteoarthritis, which is characterized by the degeneration of articular cartilage. CCN3, a member of the CCN family, is expressed in cartilage and has various physiological functions during chondrocyte development, differentiation, and regeneration. Here, we examine the role of CCN3 in cartilage maintenance. During aging, the expression of Ccn3 mRNA in mouse primary chondrocytes from knee cartilage increased and showed a positive correlation with p21 and p53 mRNA. Increased accumulation of CCN3 protein was confirmed. To analyze the effects of CCN3 in vitro, either primary cultured human articular chondrocytes or rat chondrosarcoma cell line (RCS) were used. Artificial senescence induced by H2O2 caused a dose-dependent increase in Ccn3 gene and CCN3 protein expression, along with enhanced expression of p21 and p53 mRNA and proteins, as well as SA-β gal activity. Overexpression of CCN3 also enhanced p21 promoter activity via p53. Accordingly, the addition of recombinant CCN3 protein to the culture increased the expression of p21 and p53 mRNAs. We have produced cartilage-specific CCN3-overexpressing transgenic mice, and found degradative changes in knee joints within two months. Inflammatory gene expression was found even in the rib chondrocytes of three-month-old transgenic mice. Similar results were observed in human knee articular chondrocytes from patients at both mRNA and protein levels. These results indicate that CCN3 is a new senescence marker of chondrocytes, and the overexpression of CCN3 in cartilage may in part promote chondrocyte senescence, leading to the degeneration of articular cartilage through the induction of p53 and p21.

Background/Aim: Stress reactions, especially those related to surgery, cause poor convalescence of cancer patients. β-Hydroxyβ-methylbutyrate (HMB) is known to regulate excessive inflammation in the body. The objective of this work was to investigate the capacity of HMB to suppress activation of nuclear factor-kappa B (NF-ĸB) and production of interleukin-6 (IL-6) in a human esophageal squamous cell carcinoma cell line . Materials and Methods: Cell proliferation was measured using the water-soluble tetrazolium-1 method, while tumor necrosis factor alpha (TNFα)-induced IL-6 production was measured using an enzyme-linked immunosorbent assay (ELISA) assay. Nuclear translocation of NF-ĸB was detected by immunofluorescence staining. Results: HMB did not affect cell proliferation. However, HMB suppressed the TNFα-induced increase in IL-6 production in TE-1 cells by inhibiting NF-ĸB activation. Conclusion: HMB did not influence TE-1 cell proliferation, but inhibited activation of NF-ĸB and IL-6 production. This result may be useful for improving excessive stress reactions during and after surgery.During and after cancer surgery, operative stress can promote tumor metastasis and result in poor prognoses. Notably, stress related to thoraco-laparotomy for esophageal cancer carries an extremely high risk of postoperative complications. Excessive post-surgical stress or postoperative complications, so-called second attacks, cause a cytokine storm that promotes tumor metastasis (surgical oncotaxis). Reported mechanisms underlying surgical oncotaxis include increased adrenal corticoid levels, blood coagulability, immunosuppression, and reactive oxygen species production (1-3).Usually, increased levels of cytokines, such as interleukin-1 (IL-1) or tumor necrosis factor alpha (TNFα), are observed several hours after surgery, followed by increased IL-6 or IL-8 (4, 5). TNFα, a representative inflammatory cytokine secreted in the tumor microenvironment, elicits secretion of other cytokines by activating nuclear factor-kappa B (NF-ĸB) signaling (6). NF-ĸB plays a central role in inflammatory reactions, and is the primary activator of cytokine storms (7,8). Target genes of NF-ĸB include adhesion factors, iNOS (inducible nitric oxide synthase), and other factors (9). Thus, NF-ĸB plays an important role in tumor survival, metastasis, and chemotherapy resistance. NF-ĸB is essential for promoting inflammation-related cancer. This mechanism can significantly impact chemotherapy and cancer-related surgeries (10). Therefore, NF-ĸB regulation is extremely important for cancer therapies.β-hydroxyβ-methylbutyrate (HMB), a metabolite of the branched-chain amino acid leucine that obstructs NF-ĸB (p65) function, has attracted attention for its ability to control excessive inflammatory reactions. HMB reportedly reduces inflammatory cytokine production, apoptosis, and activity of proteolysis-inducing factor (11). Thus, we hypothesized that HMB regulates activation of the ubiquitin-proteasome pathway to control NF-kB activation and excessive inflamm...

Background/Aims: It has been found experimentally and clinically that eicosapentaenoic acid (EPA) exerts an anticancer effect and that it has a minimal adverse event profile relative to other anticancer drugs. Any synergy between EPA and other anticancer drugs could be of therapeutic relevance, especially in elderly or high-risk patients. Therefore, we investigated the synergism between anticancer drugs and EPA experimentally. Methods: EPA was coadministered in vitro with various anticancer drugs (paclitaxel, docetaxel, 5-fluorouracil and cis-diamminedichloridoplatinum[II]) to TE-1 cells, which were derived from human esophageal cancer tumors. Cell proliferation was measured by the water soluble tetrazolium-1 method. Result: Sub-threshold concentrations of EPA, which alone produced no anticancer effect, caused a synergistic suppressive effect on TE-1 cell proliferation when combined with other anticancer agents. Conclusion: Coadministration of EPA with other anticancer drugs may represent a new therapeutic paradigm offering a reduced side effect profile.

Background/Aim: Eicosapentaenoic acid (EPA) inhibits NF-ĸB activation and IL-6 production in TE-1 esophageal cancer cells. NF-ĸB is related to cancer cell migration. The aim of this study is to evaluate whether EPA has a metastasis suppressing effect. Herein, we investigated EPA-treated TE-1 cell migration using TAXIScan. Materials and Methods: EZ-TAXIScan ® was used to verify whether EPA inhibits cancer cell chemotaxis. Results: Using 50% fetal bovine serum (chemoattractant) without EPA (positive control), average velocity was 0.306±0.084 μm/min compared to 0.162±0.067 μm/min without chemoattraction (negative control). Directionalities of positive and negative controls were 1.039±0.152 and 0.488±0.251 radians, respectively, indicating a significant increase in migration of the positive control compared to that of the negative control. Average velocities were 0.306±0.084 (no EPA), 0.288±0.078 (100 μM EPA), and 0.240±0.054 200 μM (EPA) μm/min, indicating that EPA reduced velocity dose-dependently. Average directionalities were 1. 039±0.152 (no EPA), 0.967±0.164 (100 μM EPA), and 0.901±0.146 (200 μM EPA) radians, indicating that EPA also inhibited directionality dose-dependently. Conclusion: EPA suppresses directional migration of TE-1 cells.

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