The novel curcumin analog FLLL32 decreases STAT3 DNA binding activity and expression, and induces apoptosis in osteosarcoma cell lines

<p>Abstract</p> <p>Background</p> <p>Curcumin is a naturally occurring phenolic compound shown to have a wide variety of antitumor activities; however, it does not attain sufficient blood levels to do so when ingested. Using structure-based design, a novel compound, FLLL32, was generated from curcumin. FLLL32 possesses superior biochemical properties and more specifically targets STAT3, a transcription factor important in tumor cell survival, proliferation, metastasis, and chemotherapy resistance. In our previous work, we found that several canine and human osteosarcoma (OSA) cell lines, but not normal osteoblasts, exhibit constitutive phosphorylation of STAT3. Compared to curcumin, we hypothesized that FLLL32 would be more efficient at inhibiting STAT3 function in OSA cells and that this would result in enhanced downregulation of STAT3 transcriptional targets and subsequent death of OSA cells.</p> <p>Methods</p> <p>Human and canine OSA cells were treated with vehicle, curcumin, or FLLL32 and the effects on proliferation (CyQUANT^®), apoptosis (SensoLyte^®Homogeneous AMC Caspase- 3/7 Assay kit, western blotting), STAT3 DNA binding (EMSA), and vascular endothelial growth factor (VEGF), survivin, and matrix metalloproteinase-2 (MMP2) expression (RT-PCR, western blotting) were measured. STAT3 expression was measured by RT-PCR, qRT- PCR, and western blotting.</p> <p>Results</p> <p>Our data showed that FLLL32 decreased STAT3 DNA binding by EMSA. FLLL32 promoted loss of cell proliferation at lower concentrations than curcumin leading to caspase-3- dependent apoptosis, as evidenced by PARP cleavage and increased caspase 3/7 activity; this could be inhibited by treatment with the pan-caspase inhibitor Z-VAD-FMK. Treatment of OSA cells with FLLL32 decreased expression of survivin, VEGF, and MMP2 at both mRNA and protein levels with concurrent decreases in phosphorylated and total STAT3; this loss of total STAT3 occurred, in part, via the ubiquitin-proteasome pathway.</p> <p>Conclusions</p> <p>These data demonstrate that the novel curcumin analog FLLL32 has biologic activity against OSA cell lines through inhibition of STAT3 function and expression. Future work with FLLL32 will define the therapeutic potential of this compound <it>in vivo</it>.</p

Genome-Wide Identification of Molecular Pathways and Biomarkers in Response to Arsenic Exposure in Zebrafish Liver

10.1371/journal.pone.0068737PLoS ONE87-POLN

DNA glycosylases: in DNA repair and beyond

The base excision repair machinery protects DNA in cells from the damaging effects of oxidation, alkylation, and deamination; it is specialized to fix single-base damage in the form of small chemical modifications. Base modifications can be mutagenic and/or cytotoxic, depending on how they interfere with the template function of the DNA during replication and transcription. DNA glycosylases play a key role in the elimination of such DNA lesions; they recognize and excise damaged bases, thereby initiating a repair process that restores the regular DNA structure with high accuracy. All glycosylases share a common mode of action for damage recognition; they flip bases out of the DNA helix into a selective active site pocket, the architecture of which permits a sensitive detection of even minor base irregularities. Within the past few years, it has become clear that nature has exploited this ability to read the chemical structure of DNA bases for purposes other than canonical DNA repair. DNA glycosylases have been brought into context with molecular processes relating to innate and adaptive immunity as well as to the control of DNA methylation and epigenetic stability. Here, we summarize the key structural and mechanistic features of DNA glycosylases with a special focus on the mammalian enzymes, and then review the evidence for the newly emerging biological functions beyond the protection of genome integrity

A cohesive crack model coupled with damage for interface fatigue problems

An semi-analytical formulation based on the cohesive crack model is proposed to describe the phenomenon of fatigue crack growth along an interface. Since the process of material separation under cyclic loading is physically governed by cumulative damage, the material deterioration due to fatigue is taken into account in terms of interfacial cohesive properties degradation. More specifically, the damage increment is determined by the current separation and a history variable. The damage variable is introduced into the constitutive cohesive crack law in order to capture the history-dependent property of fatigue. Parametric studies are presented to understand the influences of the two parameters entering the damage evolution law. An application to a pre-cracked double-cantilever beam is discussed. The model is validated by experimental data. Finally, the effect of using different shapes of the cohesive crack law is illustrate

Investigating the interactive mechanisms between surface water and groundwater over the Jhuoshuei river basin in central Taiwan

[[abstract]]In Taiwan, groundwater commonly becomes important water resources in dry periods, and/or areas lack of water storage facility due to its low cost, steady water supply and good water quality. However, improper groundwater development brings about serious decreases in groundwater levels and land subsidence which causes disasters, such as seawater intrusion or soil salination, accompanied with environmental and economic losses. It is critical to develop strategies for water resources conservation in mountainous areas. The complex heterogeneity of mountainous physiographic environment makes it challenging in the forecasts of groundwater level variations, particularly in mountainous areas. Artificial neural networks (ANNs) have been recognized as an effective modeling tool for complex nonlinear systems in the last two decades. This study aims to investigate the interactive mechanisms of groundwater at the mountainous areas of the Jhuoshuei river basin in central Taiwan through analyzing and modeling the groundwater level variations. Several issues are discussed in this study, which includes the correlation between groundwater level variation and rainfall as well as streamflow, the identification of groundwater recharge patterns and effective rainfall thresholds for estimating groundwater level variations. The results indicate: (1) the daily variation of groundwater level is closely correlated with river flow and one-day antecedent rainfall based on correlation analyses; (2) effective rainfall thresholds can be identified successfully; (3) groundwater level variations can be classified into four types for monitoring wells; and (4) the daily variations of groundwater level can be well estimated by constructed ANNs. The identified interactive mechanisms between surface water and groundwater can facilitate the mountainous water resource conservation strategy for better water management, especially irrigation water supply and for alleviating land subsidence in downstream areas in the future.[[incitationindex]]SCI[[booktype]]電子版[[booktype]]紙