Inhibitory Effect Of Phytochemicals Research Articles

Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption.

Circadian disruption has been found to increase the risk of metabolic diseases, brain disorders, and cancer. The aryl hydrocarbon receptor (AhR), responsible for xenobiotic metabolism, is known to be activated by certain environmental stimuli, including polycyclic aromatic hydrocarbons (PAHs). Exposure to these stimuli may lead to diseases related to circadian disruption, with AhR activation suggested as a leading cause. Both the aryl hydrocarbon receptor nuclear translocator (ARNT) and aryl hydrocarbon receptor nuclear translocator-like (BMAL1) are class II basic helix-loop-helix/Per-ARNT-SIM (bHLH-PAS) proteins. These proteins form heterodimers with stimulated class I bHLH-PAS proteins, including circadian locomotor output cycles kaput (CLOCK) and AhR. Due to their sequential similarity, the overactivation of AhR by toxicants, such as PAHs, may lead to the formation of heterodimers with BMAL1, potentially causing circadian disruption. Dysregulation of BMAL1 can affect a wide range of metabolic genes, emphasizing its crucial roles. However, this issue has not been adequately addressed. Previous studies have reported that the inhibitory effects of phytochemicals on AhR activation can ameliorate diseases induced by environmental toxicants. Additionally, some phytochemicals have shown preventive effects on circadian misalignment. Therefore, this Review aims to explore potential strategies to prevent circadian disruption induced by food-borne toxicants, such as benzo[a]pyrene; to generate new ideas for future studies; and to highlight the importance of investigating these preventive strategies.

Abstract 5189: Inhibitory effect of phytochemicals on oncostatin-M-induced tumor invasion and migration in human esophageal carcinoma

Abstract An epithelial-to-mesenchymal transition (EMT) is one of important phenomenon in tumor metastasis. Oncostatin-M (OSM) belonging to the IL-6 family is a cytokine that participates in invasion and migration of various cancer cells. It is produced by macrophage and stimulates the JAK/STAT signal transduction pathway. In this study, we examined the effect of OSM on EMT of human esophageal carcinoma cells and found a way to inhibit cell metastasis. We first observed morphological changes of tumor cells from an epithelial-like phenotype to a more spindle-shaped, mesenchymal phenotype by OSM. Consistent with these findings, OSM also promoted cell motility using a wound scratch assay and matrigel invasion assay. Moreover, we observed that intracellular stat3 phosphorylation was promoted by the stimulation of OSM by Western blotting. To confirm the contribution of p-stat3, we used a selective JAK2/STAT3 inhibitor cucurbitacin I. As a result, cucurbitacin I strongly inhibited OSM-induced tumor cell invasion and migration. Then, we used two dietary phytochemical resveratrol (polyphenol in grapes) and sulforaphane (isothiocyanate in broccolis), both were reported as candidates of stat3 inhibitor. By the addition of resveratrol or sulforaphane, we found that these markedly inhibited OSM-induced stat3 phosphorylation, the expression of EMT-related genes (snail, slug and vimentin) and tumor cell migration. Overall, our findings provide new evidence that these phytochemicals suppress OSM-induced tumor invasion and migration through inhibiting stat3 phosphorylation and EMT pathway. Citation Format: Eijin Naka, Yuko Takahashi, Hisahiro Matsubara, Kazunori Kato. Inhibitory effect of phytochemicals on oncostatin-M-induced tumor invasion and migration in human esophageal carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5189. doi:10.1158/1538-7445.AM2015-5189

Inhibitory effects of phytochemicals on metabolic capabilities of CYP2D6(*)1 and CYP2D6(*)10 using cell-based models in vitro.

Herbal products have been widely used, and the safety of herb-drug interactions has aroused intensive concerns. This study aimed to investigate the effects of phytochemicals on the catalytic activities of human CYP2D6(*)1 and CYP2D6(*)10 in vitro. HepG2 cells were stably transfected with CYP2D6(*)1 and CYP2D6(*)10 expression vectors. The metabolic kinetics of the enzymes was studied using HPLC and fluorimetry. HepG2-CYP2D6(*)1 and HepG2-CYP2D6(*)10 cell lines were successfully constructed. Among the 63 phytochemicals screened, 6 compounds, including coptisine sulfate, bilobalide, schizandrin B, luteolin, schizandrin A and puerarin, at 100 μmol/L inhibited CYP2D6(*)1- and CYP2D6(*)10-mediated O-demethylation of a coumarin compound AMMC by more than 50%. Furthermore, the inhibition by these compounds was dose-dependent. Eadie-Hofstee plots demonstrated that these compounds competitively inhibited CYP2D6(*)1 and CYP2D6(*)10. However, their Ki values for CYP2D6(*)1 and CYP2D6(*)10 were very close, suggesting that genotype-dependent herb-drug inhibition was similar between the two variants. Six phytochemicals inhibit CYP2D6(*)1 and CYP2D6(*)10-mediated catalytic activities in a dose-dependent manner in vitro. Thus herbal products containing these phytochemicals may inhibit the in vivo metabolism of co-administered drugs whose primary route of elimination is CYP2D6.

The Inhibitory Effect of Phytochemicals on the Oxidative DNA Damage in Lymphocytes by Chrysotile

We investigated the cytotoxicity and oxidative DNA damage by chrysotile, one of the asbestos, in this investigation. Chrysotile enhanced malondialdehyde (MDA) levels and intracellular reactive oxygen speices generation in human airway epithelial cells. Furthermore, asbestos-induced oxidative DNA damage in lymphocytes was evaluated by single cell gel electrophoresis and quantified as DNA tail moment. Notably, phytochemicals such as curcumin, berberine, and sulforaphane presented inhibitory effect on the asbestos-induced oxidative DNA damage in lymphocytes.