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Keratinocyte-fibroblast interactions are critical for skin repair after injury. During the proliferative phase of wound healing, proliferation, migration and differentiation of these cells are the major mechanisms leading to tissue remodeling. We have previously reported that glycitin, a major soy isoflavone, stimulates dermal fibroblast proliferation; and the phytochemical, 4′,6,7-trimethoxyisoflavone (TMF), induces migration of HaCaT keratinocyte cells. We therefore investigated whether these compounds display synergistic effects on skin cells during wound healing in vitro and in vivo. Co-treatment with TMF and glycitin synergistically promotes the proliferation and migration of both keratinocytes and dermal fibroblasts, with a 1:1 ratio of these compounds showing the greatest efficacy in our co-culture system. This keratinocyte-fibroblast interaction occurred via the secretion of TGF-β, and the induction of differentiation and proliferation was confirmed in both indirect and direct co-culture assays. In an excisional and burn wound animal model, mice treated with a 1:1 ratio of TMF and glycitin showed faster wound closure, regeneration and scar reduction than even the positive control drug. These data indicate that two isoflavones, TMF and glycitin, act synergistically to promote wound healing and anti-scarring and could potentially be developed together as a bioactive therapeutic for wound treatment. KCI Citation Count: 39

The antitumor activity of a novel syntheticchalcone derivative, 20-hydroxy-2,4,60-trimethoxychalcone(1H3MC), was evaluated using the multi-drug-resistanthuman uterine sarcoma MES-SA/Dx5 cells. Treatmentwith 1H3MC reduced P-glycoprotein expression in a timedependentmanner and inhibited MES-SA/Dx5 cell proliferation. Cisplatin alone had no effect on cell viability, butcombined treatment with cisplatin and 1H3MC exhibitedsynergistic cytotoxicity. Furthermore, the combination ofcisplatin and 1H3MC synergistically cleaved both caspase-3 and its substrate protein, poly(ADP-ribose) polymerase,which resulted in the fragmentation of genomic DNA, ahallmark of apoptosis. These results suggest that 1H3MC isa promising adjuvant agent for overcoming P-glycoproteinmediatedmulti-drug resistance in cancer cells. KCI Citation Count: 4

Microglial cells are the resident innate immune cells that sense pathogens and tissue injury in the central nervous system (CNS). Microglial activation is critical for neuroinflammatory responses. The synthetic compound 2-hydroxy-3',5,5'-trimethoxychalcone (DK-139) is a novel chalcone-derived compound. In this study, we investigated the effects of DK-139 on Toll-like receptor 4 (TLR4)-mediated inflammatory responses in BV2 microglial cells. DK-139 inhibited lipopolysaccharide (LPS)-induced TLR4 activity, as determined using a cell-based assay. DK-139 blocked LPS-induced phosphorylation of IκB and p65/RelA NF-κB, resulting in inhibition of the nuclear translocation and trans-acting activity of NF-κB in BV2 microglial cells. We also found that DK-139 reduced the expression of NF-κB target genes, such as those for COX-2, iNOS, and IL-1β, in LPS-stimulated BV2 microglial cells. Interestingly, DK-139 blocked LPS-induced Akt phosphorylation. Inhibition of Akt abrogated LPS-induced phosphorylation of p65/RelA, while overexpression of dominant-active p110CAAX enhanced p65/RelA phosphorylation as well as iNOS and COX2 expression. These results suggest that DK-139 exerts an anti-inflammatory effect on microglial cells by inhibiting the Akt/IκB kinase (IKK)/NF-κB signaling pathway.

2,6,6-Trimethylbicyclo[3.1.1]hept-2-ene (α-Pinene) is an organic compound of the terpene class found in the essential oil of many plants. In this study, the inhibitory effect of α-pinene on tumor invasion in highly metastatic MDA-MB-231 human breast cancer cells was evaluated. α-Pinene inhibited tumor necrosis factor (TNF)-α-induced invasiveness of MDA-MB-231 cells as revealed by three-dimensional spheroid invasion assay. Further analysis showed that α-pinene reduced TNFα-induced matrix metalloproteinase-9 gene promoter activation and mRNA expression in a dose-dependent manner. In addition, α-pinene treatment attenuated TNFα-induced nuclear factor κB (NF-κB) activation and NF-κB-dependent transcriptional activity. These results suggest that α-pinene has a significant effect on the inhibition of tumor invasion and may potentially be developed into an anti-metastatic drug.

Cisplatin often shows the drug resistance which could limit the chemotherapeutic efficacy. Thus, it is necessary to develop anticancer agents against cisplatin-resistant cancer cells. To identify pharmacophores exhibiting the cell growth inhibitory effect against cisplatin-resistant A2780/Cis ovarian cancer cells, we prepared 35 synthetic polyphenols bearing naphthalene skeleton including naphthalenyl chalcones, naphthalenyl flavones, naphthalenyl flavanones, 4,5-dihydro-1 H -pyrazol-3-yl)naphthalen-2-ols, naphthalen-1-yl- N -phenyl-4,5-dihydro-1 H -pyrazole-1-carbothioamides, and 4,5-dihydro-1 H -pyrazol-3-yl)naphthalen-1-ol. The correlation between their inhibitory effects and structural properties was evaluated using hologram quantitative structure activity relationship and comparative molecular field analysis. The pharmacophores derived here can lead us to design new polyphenols against the growth of cisplatin-resistant cells.

Fourteen diphenyl imidazoline derivatives were designed, synthesized, and identified using NMR spectroscopy and high-resolution mass spectrometry. Their cytotoxicities in HCT 116 colorectal cancer cell lines were measured using a clonogenic long-term survival assay and the half-maximal cell growth inhibitory concentration (GI 50 ) values were in the range 3.1–58.4 μM. As the anticancer effects of diphenyl imidazolines were reported to be caused by the inhibition of mouse double minute 2 homolog (MDM2), the inhibitory effects of the most potent derivative on MDM2 were assessed through Western blotting analysis. In silico docking experiments revealed the binding mode between this derivative and MDM2.

Flavonoids have always been studied in the context oftherapies of human diseases. Among them, chalcone, an openchainflavonoid, has been used as a key precursor for syntheticlead compounds due to its diverse innate biological activity. Additionally, benzoflavone is known to induce xenobiotic-metabolizingenzyme activity, as well as have potent chemopreventive activity. Therefore, the combined structure of these two compounds shouldbe useful for the discovery of new and/or increased biologicalactivity. In this study, a chalcone derivative, 2'-hydroxy-2,4,6-trimethoxy-5',6'-naphthochalcone (HMNC-74), was synthesized,and its anticancer activity was tested in the HCT116 human coloncancer cell line. An in silico docking study showed that HMNC-74 binds to tubulin. HMNC-74 exhibited the inhibition ofclonogenicity of HCT116 cells and cell cycle arrest at the G2/Mphase, followed by induction of apoptosis through, at least in part,p53-dependent caspase-7 activation. The results of this studyshow that HMNC-74 may be an effective chemotherapeutic agent. KCI Citation Count: 4

To find potent chemotherapeutic agents, cytotoxic effects of 42 synthetic chalcone derivatives bearing naphthyl groups on HCT116 human colon cancer cell lines were tested using the clonogenic long-term survival assay. The relationships between their half-maximal cell growth inhibitory concentrations (GI 50 ) and structural properties were obtained using comparative molecular field analysis and comparative molecular similarity indices analysis. The structural conditions that showed maximum cytotoxic effects on the colon cancer cells were determined. In addition, a derivative, ( E )-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one, showing the best GI 50 value, was assessed for stimulating reactive oxygen species (ROS) production. While its treatment on non-tumorigenic epithelial MCF-12A cell line did not affect the intracellular ROS levels, its treatment on MDA-MB-231 human breast cancer cell line showed ROS accumulation. These findings demonstrate that naphthalenylchalcones can be developed as potent chemotherapeutic agents.

Ultraviolet (UV) radiation in sunlight can induce skin ageing and photo-carcinogenesis. UV may also induce melanin production and wrinkle formation. Recently, natural secondary compounds have been reported to have protective effects against UV light. In this study, the effects of two different compounds, glycitin and 3-(2,4,6-trimethoxyphenyl)-2,3-dihydro-1H-benzo[f]chromen-1-one (TDB), on human dermal fibroblasts and melanocytes were investigated. At first, only TDB was used on melanocyte cells to test whether it inhibited the proliferation of these cells. Then, a mixture of glycitin and TDB was tested on human dermal fibroblasts for 48 h in order to investigate its effect on proliferation, collagen production, and metalloproteinase family expression. The TDB treatment alone not only inhibited the proliferation of melanocytes but also increased extra cellular matrix production in dermal fibroblasts and cell viability. The mixture of glycitin and TDB markedly increased fibroblast proliferation and helped to maintain fibroblast viability in the face of UV-induced and H2O2-induced damages. This co-treatment also significantly promoted collagen IV expression and accelerated total collagen secretion. In addition, the metalloproteinase (MMPs) family such as MMP1, MMP2, and MMP7 were down-regulated at the transcriptional level. In conclusion, the mixture of glycitin and TDB induced fibroblast proliferation even when these fibroblasts were damaged by UV exposure and H2O2, whereas augmented collagen production and the inhibition of MMPs reduced wrinkle formation and decreased melanocyte proliferation, suggesting a potential use in UV-protective therapy.

A methoxylated flavanone derivative, 2′,3′,4′-trimethoxy-5,6-naphthoflavanone (TMNF), was synthesized, and its anti-proliferative activity was evaluated. In HCT116 colon cancer cells, TMNF inhibited cellular proliferation and triggered cytotoxicity. A flow cytometry assay showed that TMNF caused cell cycle arrest at the G2/M phase with a concomitant decrease in the population of G1 phase cells. Furthermore, TMNF caused accumulation of p53 and its downstream target, Bax, and stimulated cleavage of caspase-7 and poly(ADP-ribose) polymerase. These data suggest that methoxylated naphthoflavanone can be an attractive pharmacophore for further development of therapeutic adjuvants.