Assessment of the anti-invasion potential and mechanism of select cinnamic acid derivatives on human lung adenocarcinoma cells.

Patients with lung adenocarcinoma are often diagnosed with metastasizing symptoms and die of early and distal metastasis. Metastasis is made up of a cascade of interrelated and sequential steps, including cell adhesion, extracellular matrix degradation, cell movement, and invasion. Hence, substances carrying the ability to stop one of the metastasis-associated steps could be a potential candidate for preventing tumor cells from metastasizing and prolonging the life of cancer patients. Cinnamic acid (CA) was demonstrated to be such a candidate for human lung adenocarcinoma cells. Nevertheless, the effectiveness of CA derivatives on invasion of lung cancer cells is still unclear. The aims of this study were to explore the mechanisms underlying several select CA derivatives against invasion of human lung adenocarcinoma A549 cells. The results revealed that caffeic acid (CAA), chlorogenic acid (CHA), and ferulic acid (FA) can inhibit phorbol-12-myristate-13-acetate (PMA)-stimulated invasion of A549 cells at a concentration of ≥100 µM. The MMP-9 activity was suppressed by these compounds through regulating urokinase-type plasminogen activator (uPA), tissue inhibitor of metalloproteinase (TIMP)-1, plasminogen activator inhibitor (PAI)-1, and PAI-2; the cell-matrix adhesion was decreased by CAA only. The proposed molecular mechanism involved not only decreasing the signaling of MAPK and PI3K/Akt but also inactivating NF-κB, AP-1, and STAT3. In the present study, we selected CAA, CHA, and FA as potential inhibitors for invasive behaviors of human lung adenocarcinoma cells and disclosed the possible mechanisms. The association between structural features and anti-invasive activity of these compounds cannot be determined here and needs to be further verified.

Molecular mechanism depressing PMA-induced invasive behaviors in human lung adenocarcinoma cells by cis- and trans-cinnamic acid.

Dietary polyphenols have been reported as an effective phytochemical for health protection and cinnamic acid (CA) is one of the polyphenols that has been demonstrated having chemopreventive potential. It was known that the early and distal metastasis might lead to the high mortality of patients with lung adenocarcinoma. We previously compared and verified the inhibitory effect of cis-CA and trans-CA on phorbol-12-myristate-13-acetate (PMA)-induced invasion of human lung adenocarcinoma A549 cells. The aim of this study was to explore the underlying molecular mechanism. By gelatin zymography and semi-quantitative RT-PCR, the activities and mRNA of MMP-9/MMP-2 exerted a significantly (p<.05) dose-dependent reduction by treating with cis-CA and trans-CA. Western blots further showed that the cis-CA- and trans-CA-inhibited MMPs might partly through modulating TIMP-1 and the PAI-2-regulated uPA activity. In molecular level, the AP-1 and NF-κB as well as the downstream of the MAPK pathway might be involved in cis-CA- and trans-CA-inhibited MMPs expression. This study disclosed the molecular mechanism underlying the anti-invasive activity of cis-CA and trans-CA and concluded the cis- and trans-form of CA should be a safe and potential agent to prevent lung tumor cells from metastasizing.

A comparative study on the effectiveness of cis- and trans-form of cinnamic acid treatments for inhibiting invasive activity of human lung adenocarcinoma cells.

Lung cancer is the major cause of tumor-related death, and approximately 70% of lung cancer patients die from metastasis. Evidence that phenolic compounds may have a potential inhibitory effect on cancer invasion and metastasis is increasingly being reported in the scientific literature. Cinnamic acid is a member of phenolics which having several isoforms in nature. The trans-cinnamic acid (t-CA) has been investigated extensively for its potential pharmacological effects whereas the study of cis-cinnamic acid (c-CA) is limited because pure c-CA was hard to obtain. We had developed a practicable method previously to transform and obtain pure c-CA, and the pure compound was used to evaluate the anti-invasive effect on human adenocarcinoma A549 cells. The A549 cells were treated with 0-200 µM of c-CA and t-CA in the presence of 200 nM phorbol-12-myristate-13-acetate (PMA) at 37 °C for 24 h, and matrix metalloproteinase (MMP)-2, MMP-9, adhesive, migratory, and invasive activities of the cells were determined. The results showed that the treatment of c-CA and t-CA dose-dependently reduced the PMA-induced MMP-2 and -9 activities but without significant effect on the adhesive activity of cells. The PMA-induced motility was suppressed in a dose-dependent manner by a 24-h treatment with c-CA and t-CA. The invasive ability was significantly (p<0.05) reduced to 68% and 65%, respectively, relative to PMA treatment alone after treatment of PMA-treated A549 cells with either 50 µM c-CA or 100 µM t-CA for 24 h. The results suggest that both of the c-CA and t-CA are inhibitors for invasion of A549 cells and the activity of c-CA seems to be higher than t-CA.

Transformation of cinnamic acid from trans- to cis-form raises a notable bactericidal and synergistic activity against multiple-drug resistant Mycobacterium tuberculosis.

Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis. The long course of treatments on TB with a combination of antibiotics leads unfavorable side effects and poor patient compliance which contributes to sustaining multiple-drug resistant tuberculosis (MDR-TB). Therefore, the development of a new effective drug or synergist to reduce the prevalence of MDR-TB is urgent to date. Cinnamic acid (CA) is a natural occurring phenolic compound with anti-microbial activity. Both trans- and cis-isoforms of CA exist in planta, and cis-cinnamic acid (c-CA) can be transformed from trans-cinnamic acid (t-CA) under sunlight. Due to the unavailability of c-CA, the literature regarding the biological functions of c-CA is still limited. We had previously developed a practicable method for the transformation of c-CA from t-CA and the isolation of c-CA. Using the techniques, sufficient c-CA was obtained to evaluate its antituberculosis activity against a MDR M. tuberculosis strain. Moreover, the synergistic effects of c-CA and t-CA with two first-line anti-TB antibiotics, isoniazid (INH) and rifampicin (RIF), were also determined. Although both of c-CA and t-CA decreased the viability of MDR-TB bacilli in a dose-dependent manner, the antituberculosis activity of c-CA was approximately 120-fold of t-CA. Furthermore, the c-CA exhibited higher synergistic effect with INH or RIF against tuberculosis than t-CA. The micrographs of scanning electron microscope (SEM) display that c-CA caused an injury on the out-layer of MDR-TB bacilli. The c-CA might be a potential anti-mycobacterial or synergistic agent that can be developed to against tuberculosis.

Chlorophyll a, an active anti-proliferative compound of Ludwigia octovalvis, activates the CD95 (APO-1/CD95) system and AMPK pathway in 3T3-L1 cells.

Ludwigia octovalvis is an aquatic plant widely distributed in Taiwan. It is traditionally used as a diuretic and is consumed as health drink. In this study, we evaluated the anti-proliferative activity of extracts and active constituent (chlorophyll a; CHL-a) of L. octovalvis in 3T3-L1 adipocytes; its mode of action on apoptosis was also investigated. Results showed that, among the different extracts and fractions, the ethylacetate layer (EAL) possessed the most potent anti-proliferative activity. Activity guided fractionation of the EAL obtained the bioactive constituent CHL-a (IC50: 24.10+/-0.83 nM). At concentrations 5-30 nM, CHL-a exhibited a dose-dependent accumulation of the Sub-G1 peak and caused cell cycle arrest at the G0/G1 phase. At 30 nM, it significantly reduced the cell viability, induced the appearance of DNA fragments, and enhanced the activation of caspase-3. Western blot data revealed that CHL-a decreased the level of Bcl-2, and increased the expression of CD95 (APO-1/CD95) and Bax. Furthermore, CHL-a up-regulated the AMPK and p-AMPK levels, and down-regulated the expression of PPAR-gamma. These results conclude that CHL-a possesses potent anti-proliferative activity, and its apoptotic effects on 3T3-L1 adipocytes are mediated through the activation of CD95 (APO-1/CD95) system and the AMPK signaling pathway.

[Research on cooperation between Streptococcus mutans and Lactobacilli in dental caries lesion].

OBJECTIVE: To analyze the count of Streptococcus mutans (S. mutans) and Lactobacilli (LB) in different groups and the cases in dental caries. To research the synergistic effect of S. mutans and LB in the process of dental caries. METHODS: 110 cases with dental caries were selected and divided according to the different degree of caries, nature and ages. To culture bacteria in the selective culture medium, then count the number of colonies. The detection rate of two kinds of bacteria in different groups, means of the bacteria count and the cariogenic cases were analyzed. RESULTS: The means of the two bacteria count increased along with the degree of caries increased (P < 0.05), and increased in the older group (P < 0.05) and the active stage (P < 0.05). The cases of two bacteria increased with the degree of caries increased (P < 0.05), and increased in the older group (P < 0.05). But there were no significant differences in evolution period and arrested caries. CONCLUSION: The pathopoiesis capability of S. mutans and LB enhanced with the extent of caries increased. In the older group, their synergism role play a lead position. In evolution period and arrested caries, S. mutans and LB were difference only in quantity and their solo cariogenic potential all enhanced in active stage, but there were not correlation on pathopoiesis capability and active or stationary phase.