Goji Ferment Ameliorated Acetaminophen-Induced Liver Injury in vitro and in vivo.

This study aimed to investigate the hepatoprotective effects of lyophilized powder of goji ferment (LPGF) against acetaminophen (APAP)-induced hepatic damage in Hep3B cells and in mice. Eleven strains of lactic acid bacteria (LAB) were selected and their hepatoprotection against APAP-induced cellular damage in Hep3B cell line was evaluated. Four strains of LAB, including BCRC11652 (Leuconostoc mesenteroides subsp. mesenteroides), BCRC14619 (Lactobacillus gasseri), KODA-1 (Pediococcus acidilactici), and KODA-2 (Limosilactobacillus fermentum), have hepatoprotective potential against APAP in vitro. Goji significantly stimulated the growth of individual and combined strains of LAB and the optimal fermented condition was the treatment of goji at 10% (w/w) for 24 h. The prepared lyophilized powder of goji ferment (LPGF) containing fifteen combinations of LAB strains was used to explore their hepatoprotection in vitro. LPGF containing all combinations of LAB strains, except for KODA-2, significantly restored APAP-reduced cell viability and improved APAP-increased cellular levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In mice model, LPGF containing BCRC11652, BCRC14619, and KODA-2 was chosen to evaluate its hepatoprotection against APAP-induced liver injury. LPGF at diverse doses have a tendency but no significant improvement on APAP-reduced body weight gain and liver weight. LPGF significantly decreased APAP-increased serum ALT and AST levels in a dose-dependent manner. At the end of experiment, LPGF significantly and dose-dependently reversed APAP-reduced activities of GSH and antioxidant enzymes, including glutathione peroxidase, superoxide dismutase, and catalase in hepatic tissue. Overall, LPGF was demonstrated to exhibit hepatoprotection against APAP-induced liver injury in vitro and in vivo.

Organochlorine pesticide residue in Chinese herbal medicine.

Over ten-year routine inspection results on organochlorine pesticide (OCP) residue were summarized, OCPs residues, including BHC isomers (α, ß, γ, and δ-BHC), DDT analogs (p,p'-DDD, p,p'-DDE, o,p'-DDT, and p,p'-DDT), and pentachloronitrobenzene (PCNB) and its metabolites (pentachloroaniline and methyl pentachlorophenyl sulfide (MPCPS)), in 1,665 samples for 37 types of Chinese herbal medicine (CHM) using the QuEChERS method coupled with the GC-ECD. Based on the maximal residue levels for OCPs set by Asian pharmacopeias, PCNB contamination in Ginseng radix as well as the total DDT and PCNB contamination in Panacis quinquefolii radix are of concern. OCP residues in different parts of Panax ginseng were also compared. The total BHC residue in leaf and fibrous root, as well as the total DDT and PCNB residue in all parts, exceeded MRL of 0.1 mg/kg. Overall, this study provided meaningful results about OCP residue in CHM for pharmaceutical industries and consumers.

Effects of Physical Properties and Processing Methods on Astragaloside IV and Flavonoids Content in Astragali radix.

The aim of this study was to investigate the effects of the physical properties (diameter size, powder particle size, composition of bark- and wood-tissue, and turnover rate) and processing methods on the content of active ingredients in Astragali radix (AR), a popular Chinese herbal medicine. The astragaloside IV and flavonoid contents increased with decreasing diameter size. Bark-tissue had significantly higher astragaloside IV and formononetin content than that in the wood-tissue. As a higher proportion of bark-tissue is associated with decreasing diameter, a strong correlation was also shown between bark- to wood-tissue ratio and active ingredients' content. Furthermore, an increase in astragaloside IV content was observed in thin powder as compared to coarse powder ground from the whole root. However, this association between active ingredients' content and powder particle size was abolished when isolating bark- and wood-tissue individually. Moreover, AR stir-frying with refined honey, a typical processing method of AR, increased formononetin content. The turnover rate of active constituents upon decoction ranged from 61.9-81.4%. Assessing the active constituent contents using its physical properties and processing methods allows for a more comprehensive understanding of optimizing and strengthening the therapeutic potentials of AR used in food and herbal supplements.

Investigation of toxic heavy metals content and estimation of potential health risks in Chinese herbal medicine.

The content of toxic heavy metals (THMs), including lead (Pb), arsenic (As), cadmium (Cd), and mercury (Hg), was determined in a total of 10,245 samples for 279 types of Chinese herbal medicine (CHM) using a validated inductively coupled plasma mass spectrometry method. The exceeding rate (ER) for the four THMs were calculated based on diverse permissible limits (PLs) established by different organizations and national pharmacopeias. Cluster analysis was used to classify the degree risk of THMs contamination according to the calculated ER. Results revealed that Cibotii rhizome, Selaginellae herba, Morindae officinalis radix, Asprellae ilicis radix, and Toxicodendri resina exhibited high-degree risk of Pb contamination. Eckloniae/Laminariae thallus, Spirodelae herba, and Naturalis indigo possessed high-degree risk of As contamination. Tetrapanacis medulla, Centipedae herba, Cyathulae radix, Linderae radix, Meretricis/Cyclinae concha, and Tabanus displayed high-degree risk of Cd contamination. Toxicodendri resina has high-degree risk of Hg contamination. In addition, six types of CHM, including Asprellae ilicis radix, Toxicodendri resina, Eckloniae/Laminariae thallus, Fossilia Ossis Mastodi, Haematitum, and Hedyotidis diffusae herba, may have non-carcinogenic health risk after consumption of raw materials because the calculated hazard quotient and hazard index were over 1.0. In summary, these data provide useful information about THMs contamination in CHM.

Dihydromyricetin-rich herbal mixture extracts as a potential prescription for treatment of metabolic syndrome in rats fed a high-fat diet and subacute toxicity assessment in rats.

Dihydromyricetin (DHM)-rich herbal mixture extracts, also called APF complex, comprised of Ampelopsis grossedentata, Pericarpium citri reticulatae, and Fructus crataegi. The content of DHM in APF complex was 362.7 ±â€¯12.5 mg/g. The aims of this study were to investigate the therapeutic effects of APF complex on metabolic syndrome in rats fed a high-fat diet (HFD) and evaluate the subacute toxicity of APF complex in rats. HFD significantly increased body weight gain, fat tissue (epididymal fat, mesenteric fat, and perirenal fat) deposition, body fat index, and hepatic triglyceride (TG) and total cholesterol (TC) accumulation as well as caused abnormal blood biochemical parameters, including TC, TG, low-density lipoprotein-cholesterol (LDL-C), free fatty acid (FFA), and glucose. APF complex has a tendency but not significance to limit HFD-induced body weight gain. APF complex also significantly improved HFD-induced body fat accumulation, as evidenced by decreasing fat tissue deposition and body fat index. In addition, APF complex significantly ameliorated HFD-induced hyperlipidemia and hyperglycemia, as evidenced by reducing levels of blood TG and TC as well as blood glucose and FFA, respectively. Furthermore, APF complex significantly decreased HFD-induced hepatic TG and TC accumulation. In subacute toxicity assessment, APF complex exhibited no toxicological signs, as evidenced by without affecting mortality, food and water consumption, body weight changes, absolute organ weights, hematological system, blood lipids and nutritional status, and electrolyte balance as well as non-toxic to liver and renal function. Overall, APF complex was considered as a non-toxic herbal prescription and could act as adjuvant therapy for metabolic syndrome.

Investigation of aflatoxins contamination in herbal materia medica in a Taiwan pharmaceutical factory.

During the years 2005-2016, a total of 1067 samples for 24 types of herbal materia medica were investigated for the presence of aflatoxins (AFs) using immunoaffinity column cleanup and HPLC-coupled to a fluorescence detector after post-column derivatization. AFs were detected in 373 (35%) out of the total samples. Among them, Platycladi Semen (65% for total AFs and 79% for AFB1), Corydalis Rhizoma (53% for total AFs and 32% for AFB1), Corni Fructus (3% for total AFs), Coicis Semen (3% for total AFs and AFB1), Nelumbinis Semen (6% for total AFs and 9% for AFB1), Arecae Semen (18% for AFB1), Polygalae Radix (5% for total AFs and AFB1), and Cassiae Semen (25% for total AFs and 38% for AFB1) exceeded the official limits of 5 and 10 µg/kg, for AFB1 and total AFs (the sum of AFB1, AFB2, AFG1, and AFG2), respectively, set by the Taiwan government. We concluded that Platycladi Semen, Corydalis Rhizoma, and Cassiae Semen are the most commonly contaminated by AFs.

Effects of herbal mixture extracts on obesity in rats fed a high-fat diet.

The aim of this study was to investigate and compare the effects of three herbal mixture extracts on obesity induced by high-fat diet (HFD) in rats. The prescriptions-Pericarpium citri reticulatae and Fructus crataegi-were used as matrix components and mixed with Ampelopsis grossedentata, Salvia miltiorrhiza, and epigallocatechin-3-gallate (EGCG) to form T1, T2, and T3 complexes, respectively. Results revealed that HFD feeding significantly increased body weight gain, fat deposition, plasma lipid profiles, hepatic lipid accumulation, and hepatic vacuoles formation, but decreased plasma levels of adiponectin in rats. Only the T1 complex showed the tendency, although not significantly so, for decreased HFD-induced body weight gain. T1 and T3 complexes significantly reduced HFD-induced fat deposition, and plasma levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol. Only the T1 complex significantly increased HFD-reduced adiponectin levels in plasma, but decreased HFD-increased triglyceride content in liver tissues. All complexes effectively inhibited HFD-induced vacuoles formation. The content of dihydromyricetin, salvianolic acid B, and EGCG in T1, T2, and T3 complexes was 18.25 ± 0.07%, 22.20 ± 0.10%, and 18.86 ± 0.04%, respectively. In summary, we demonstrated that herbal mixture extracts, especially T1 complex, exhibit antiobesity activity in HFD-fed rats.

The anti-angiogenic action of 2-deoxyglucose involves attenuation of VEGFR2 signaling and MMP-2 expression in HUVECs.

AIMS: 2-Deoxyglucose (2-DG) is a glucose analogue and has been shown to inhibit angiogenesis in human umbilical vascular endothelial cells (HUVECs) through interference with N-linked glycosylation. However, the anti-angiogenic mechanisms of 2-DG are not fully elucidated. MAIN METHODS: We first employed an ex vivo rat aortic ring model to substantiate the anti-angiogenic action of 2-DG and then used HUVECs to investigate the molecular mechanism underlying such an action. KEY FINDINGS: Results reveal that 2-DG (0.05-1.0mM) significantly inhibited tube formation in both rat aortic rings and HUVECs. 2-DG (0.1-1.0mM) also significantly inhibited cell invasion and migration, as well as the activity and mRNA and protein expression of matrix metalloproteinase (MMP)-2 in HUVECs. In addition, 2-DG (1.0mM) significantly inhibited mRNA and protein expression of vascular endothelial growth receptor 2 (VEGFR2) in a time-dependent manner. 2-DG also significantly inhibited the phosphorylation of the focal adhesion kinase (FAK) and mitogen-activated protein kinase (p38), the downstream molecules of VEGFR2. The effects of 2-DG on tube formation, MMP-2 activity, and VEGFR2 protein expression in HUVECs were reversed by mannose, an N-linked glycosylation precursor. Mannose also reversed 2-DG-induced accumulation of VEGFR2 in the endoplasmic reticulum. SIGNIFICANCE: This ex vivo and in vitro study demonstrates that 2-DG inhibits angiogenesis with an action involving attenuation of VEGFR2 signaling and MMP-2 expression, possibly resulting from interference with N-linked glycosylation of VEGFR2. Further studies are needed to show that 2-DG inhibits VEGF-mediated angiogenesis or that the actual status of N-glycosylation of VEGFR2 is affected by the treatment.

Gastroprotective potential against indomethacin and safety assessment of the homology of medicine and food formula cuttlebone complex.

Cuttlebone complex (CBC), a homology of medicine and food formula, is comprised of five herbal medicines (Endoconcha Sepiae, Radix Paeoniae Rubra, fresh ginger, Fructus Amomi, and Radix Glycyrrhizae) and two food ingredients (Zingiber zerumbet and chitosan). Herein, the gastroprotective potential against indomethacin and a safety assessment of CBC were investigated. In a gastroprotective model, CBC effectively decreased the indomethacin-increased gastric ulcerous lesions, and increased the indomethacin-decreased prostaglandin E2 levels in the gastric mucosa. In genotoxicity tests, CBC treatment did not increase the numbers of revertant colonies in five Salmonella typhimurium strains and chromosome aberrations in Chinese hamster ovary CHO-K1 cells, with or without S9 metabolic activation. The oral supplementation of CBC did not increase micronucleus formation in the peripheral blood of mice. In a subacute toxicity study, the body weight and blood biochemical parameters observed in CBC-treated rats were normal. In conclusion, CBC was considered as a non-toxic formula and could be used to remedy indomethacin-induced gastric damage.

Multicarotenoids at Physiological Levels Inhibit Metastasis in Human Hepatocarcinoma SK-Hep-1 Cells.

Several studies have demonstrated that single carotenoid, including lycopene, ß-carotene, and α-carotene, exhibits antimetastatic effects; however, little is known whether multicarotenoids have similar effects. Herein, we investigated the antimetastatic effect of multicarotenoids at physiological serum levels in Taiwanese (MCT at 1.4 µM) and American (MCA at 1.8 µM) populations using human hepatocarcinoma SK-Hep-1 cells in comparison with single carotenoid, such as lycopene (0.3 or 0.6 µM, respectively), α-carotene (0.1 µM), ß-carotene (0.4 µM), lutein (0.4 or 0.5 µM, respectively), and ß-cryptoxanthin (0.2 µM). Results reveal that MCA treatment exhibited an additive inhibition on invasion, migration and adhesion at 24 and 48 h of incubation, whereas MCT treatment possessed additive inhibition at 48 h of incubation. The antimetastatic action of MCT and MCA involved additive reduction on activities of matrix metalloproteinase (MMP)-2, -9, and protein expression of Rho and Rac 1 but additive promotion on protein expression of tissue inhibitor of MMP (TIMP)-1 and -2. All of these effects were stronger in MCA than in MCT at 24 and 48 h of incubation. These results demonstrate that multi-carotenoids effectively inhibit metastasis of human hepatocarcinoma SK-Hep-1 cells. More in vivo studies are needed to confirm these findings.

Alpha-carotene inhibits metastasis in Lewis lung carcinoma in vitro, and suppresses lung metastasis and tumor growth in combination with taxol in tumor xenografted C57BL/6 mice.

This study aimed to investigate the anti-metastatic activity of α-carotene (AC) in Lewis lung carcinoma (LLC) and in combination with taxol in LLC-xenografted C57BL/6 mice. Cell culture studies reveal that AC significantly inhibited invasion, migration and activities of matrix metalloproteinase (MMP)-2, -9 and urokinase plasminogen activator but increased protein expression of tissue inhibitor of MMP (TIMP)-1, -2 and plasminogen activator inhibitor (PAI)-1. These effects of AC are similar to those of ß-carotene at the same concentration (2.5 µM). AC (2.5 µM) also significantly inhibited integrin ß1-mediated phosphorylation of focal adhesion kinase (FAK) which then decreased the phosphorylation of MAPK family. Findings from the animal model reveal that AC treatment (5m g/kg) alone significantly decreased lung metastasis without affecting primary tumor growth, whereas taxol treatment (6 mg/kg) alone exhibited significant inhibition on both actions, as compared to tumor control group. AC treatment alone significantly decreased protein expression of integrin ß1 but increased protein expression of TIMP-1 and PAI-1 without affecting protein expression of TIMP-2 and phosphorylation of FAK in lung tissues, whereas taxol treatment alone significantly increased protein expression of TIMP-1, PAI-1 and TIMP-2 but decreased protein expression of integrin ß1 and phosphorylation of FAK. The combined treatment produced stronger actions on lung metastasis and lung tissues protein expression of TIMP-1, TIMP-2 and PAI-1. Overall, we demonstrate that AC effectively inhibits LLC metastasis and suppresses lung metastasis in combination with taxol in LLC-bearing mice, suggesting that AC could be used as an anti-metastatic agent or as an adjuvant for anti-cancer drugs.

Anti-metastatic effects of antrodan, the Antrodia cinnamomea mycelia glycoprotein, in lung carcinoma cells.

This study investigated the anti-metastatic effects of antrodan, the glycoprotein from Antrodia cinnamomea (AC) mycelia, through direct actions and indirect immunomodulatory effects in Lewis lung carcinoma (LLC). Antrodan was isolated from AC mycelia by alkali extraction, acid precipitation, and purification using sepharose CL-6B column chromatography. In the direct anti-metastatic action, antrodan (30-70 µg/mL) was found to significantly inhibit invasion and migration of LLC cells, and these effects involved up-regulation of tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2, and nm23-H1 protein expression leading to decreased activities and protein expression of MMP-2 and MMP-9. For testing the indirect immunomodulatory effect, antrodan was incubated for 3d with mononuclear cells (MNCs) isolated from human peripheral blood to obtain the condition medium (CM). Antrodan significantly increased interleukin (IL)-12 and IL-1ß levels, but decreased TNF-α, IL-6 and IL-8 levels in the MMC-CM, which also significantly inhibited invasion, migration, and the activities and protein expression of MMP-2 and MMP-9, but significantly increased protein expression of TIMP-1, TIMP-2, and nm23-H1 in LLC cells. The indirect immunomodulatory effect of antrodan was stronger than the direct anti-metastatic effect at the same concentrations (50 and 60 µg/mL). Overall, the results suggest the anti-metastatic potential of antrodan in LLC cells.

Vitamin C protects against cisplatin-induced nephrotoxicity and damage without reducing its effectiveness in C57BL/6 mice xenografted with Lewis lung carcinoma.

Vitamin C (vit C) has been shown to diminish cisplatin (CP)-induced nephrotoxicity and oxidative damage in healthy rats and mice. However, little is known whether vit C has similar actions and enhances the anticancer effect of CP in tumor-bearing mice. Herein, C57BL/6 mice were implanted (s.c.) with Lewis lung carcinoma (LLC) for 9 days before intraperitoneal administration with CP (5 mg/kg) in the presence or absence of low- (200 mg/kg) and high- (1000 mg/kg) dose vit C twice a week for an additional 28 days. Results reveal that vit C or CP treatment alone significantly inhibited tumor growth, although vit C in combination with CP did not further inhibit tumor growth, as compared to CP treatment alone. In addition, CP significantly induced nephrotoxicity and oxidative damage, as evidenced by increased plasma levels of blood urea nitrogen and creatinine as well as levels of lipid peroxidation and carbonyls, decreased ratios of GSH/GSSG in liver and kidney. Vit C significantly reversed these undesirable side effects induced by CP, and most of these actions of vit C were dose-dependent. Overall, we conclude that vit C can protect against CP-induced nephrotoxicity and damage without reducing CP's effectiveness in LLC-bearing mice.

Antimetastatic effects of α-carotene and possible mechanisms of action in human hepatocarcinoma SK-Hep-1 cells.

In vitro evidence suggests that α-carotene (AC) is an antimetastatic agent against cancer cells, but the mechanistic action is unclear. This study investigated the antimetastatic effect and possible mechanism of AC in comparison with ß-carotene (BC) using human hepatocarcinoma SK-Hep-1 cells. Results reveal that treatment with AC (0.5-2.5 µM) for 48 h significantly inhibited invasion, migration, and adhesion of SK-Hep-1 cells in a concentration-dependent manner. These effects of AC were stronger than those of BC at the same concentration (2.5 µM). Mechanistically, AC significantly decreased activities of urokinase plasminogen activator and matrix metalloproteinases (MMP)-2 and -9, but increased protein expression of plasminogen activator inhibitor-1, tissue inhibitor of MMP (TIMP)-1 and -2, and nm23-H1, an antimetastatic protein. AC also attenuated focal adhesion kinase-mediated phosphorylation of mitogen-activated protein kinase family resulting in decreased protein expression of Rho and Rac 1. Overall, these data suggest that AC has potential as an antimetastatic agent.

Complexation of fluorescent tetraphenylthiophene-derived ammonium chloride to poly(N-isopropylacrylamide) with sulfonate terminal: aggregation-induced emission, critical micelle concentration, and lower critical solution temperature.

Amphiphilic polymers with hydrophilic poly(N-isopropylacylamide) (PNIPAM) shell connecting hydrophobic tetraphenylthiophene (TP) core, which has the novel aggregation-induced emission (AIE) property, by ionic bonds were prepared to explore the AIE-operative emission responses toward critical micelle concentration (CMC) and lower critical solution temperature (LCST). To exercise the idea, ammonium-functionalized TP2NH(3)(+) and sulfonate-terminated PNIPAM were separately prepared and mixed in different molar ratios to yield three amphiphilic TP-PNIPAMn complexes for the evaluations of CMC and LCST by fluorescence responses. The nonemissive dilute aqueous solutions of TP-PNIPAMn became fluorescent when increasing concentrations above CMC. Heating micelles solution to temperatures above LCSTs causes further enhancement on the emission intensity. The fluorescence responses are explained by the extent of aggregation in the micelles and in the globules formed at room temperature and at high temperatures, respectively.

Dynamic strain measured by Mach-Zehnder interferometric optical fiber sensors.

Optical fibers possess many advantages such as small size, light weight and immunity to electro-magnetic interference that meet the sensing requirements to a large extent. In this investigation, a Mach-Zehnder interferometric optical fiber sensor is used to measure the dynamic strain of a vibrating cantilever beam. A 3 × 3 coupler is employed to demodulate the phase shift of the Mach-Zehnder interferometer. The dynamic strain of a cantilever beam subjected to base excitation is determined by the optical fiber sensor. The experimental results are validated with the strain gauge.

Lycopene inhibits angiogenesis both in vitro and in vivo by inhibiting MMP-2/uPA system through VEGFR2-mediated PI3K-Akt and ERK/p38 signaling pathways.

SCOPE: Limited in vitro data show that lycopene may be anti-angiogenic but with unclear mechanisms. Here, we employed ex vivo and in vivo assays to substantiate the anti-angiogenic action of lycopene and determined its molecular mechanisms in human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: The anti-angiogenic activity of lycopene was confirmed by ex vivo rat aortic ring and in vivo chorioallantoic membrane assays. Furthermore, the in vivo matrigel plug assay in mice demonstrated that lycopene implanted s.c. at the highest dose used (400 µg/plug) completely inhibited the formation of vascular endothelial cells induced by vascular endothelial growth factor (VEGF). As expected, lycopene inhibited tube formation, invasion, and migration in HUVECs, and such actions were accompanied by reduced activities of matrix metalloproteinase-2, urokinase-type plasminogen activator, and protein expression of Rac1, and by enhancing protein expression of tissue inhibitors of metalloproteinase-2 and plasminogen activator inhibitor-1. Moreover, lycopene attenuated VEGF receptor-2 (VEGFR2)-mediated phosphorylation of extracellular signal-regulated kinase (ERK), p38, and Akt as well as protein expression of PI3K. CONCLUSION: Our data demonstrate the anti-angiogenic effect of lycopene both in vitro and in vivo. The anti-angiogenic activity of lycopene may involve inhibition of MMP-2/uPA system through VEGFR2-mediated PI3K-Akt and ERK/p38 signaling pathways.

Diverse effects of ß-carotene on secretion and expression of VEGF in human hepatocarcinoma and prostate tumor cells.

Oral administration of ß-carotene (BC) was found to exert opposite effects on plasma levels of vascular endothelial growth factor (VEGF) in two animal models. One study in nude mice injected via tail vein with hepatocarcinoma SK-Hep-1 cells showed that BC decreases the plasma VEGF level, whereas the other study in nude mice injected subcutaneously with prostate tumor PC-3 cells showed that BC increases the plasma VEGF level. Herein we investigated whether BC (0.5-20 µM) possesses diverse effects on VEGF secretion in SK-Hep-1, PC-3 and melanoma B16F10 cells. We found that incubation of SK-Hep-1 cells with BC (1-20 µM) for 6 h significantly decreased VEGF secretion, whereas BC (1-10 µM) significantly increased the VEGF secretion in PC-3 cells. However, these effects disappeared at 12 h of incubation. Similar effects occurred in VEGF mRNA and protein expression after treatment of SK-Hep-1 and PC-3 cells with BC for 6 h. In contrast, BC (0.5-20 µM) did not affect mRNA and protein expression and secretion of VEGF in B16F10 cells. We also found that the proliferation of SK-Hep-1 and B16F10 cells was significantly inhibited by 20 µM BC at 6 and 12 h of incubation, whereas the proliferation of PC-3 cells was significantly inhibited by 20 µM BC at 12 h of incubation. In summary, the present study demonstrated the tumor-specific effect of BC on VEGF secretion in different cancer cell lines.

Apo-8'-lycopenal induces expression of HO-1 and NQO-1 via the ERK/p38-Nrf2-ARE pathway in human HepG2 cells.

Lycopene and its metabolite apo-10'-lycopenoic acid have been shown to induce phase II detoxifying/antioxidant enzymes through activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2)-antioxidant response element (ARE) transcription system. However, little is known about whether apo-8'-lyocpenal, one of the main metabolites of lycopene in rat livers, in lycopene-containing food, and in human plasma, has similar effects. This study investigated the effect of apo-8'-lycopenal on Nrf2-ARE system-mediated heme oxygenase 1 (HO-1) and NAD(P)H:quinine oxidoreductase 1 (NQO-1) expression in human HepG2 cells. It was found that apo-8'-lycopenal (1-10 µM) significantly increased nuclear Nrf2 accumulation, ARE-luciferase activity, Nrf2-ARE binding activity, chymotrypsin-like activity, and downstream HO-1 and NQO-1 expression, but decreased cytosolic Kelch-like ECH-associated protein 1 (Keap1) expression. Results also revealed that the ERK/p38-Nrf2 pathway is involved in activation of HO-1 and NQO-1 expression by apo-8'-lycopenal using Nrf2 siRNA and ERK/p38 specific inhibitors. In addition, the activation time of lycopene on nuclear Nrf2 accumulation is slower than that of apo-8'-lycopenal, suggesting that the chemopreventive effects of lycopene may be partially attributed to its metabolites.

Antimetastatic effects and mechanisms of apo-8'-lycopenal, an enzymatic metabolite of lycopene, against human hepatocarcinoma SK-Hep-1 cells.

Lycopene is primarily metabolized by carotenoid monoxygenase II into apo-8'- and apo-12'-lycopenal in the rat liver. Although lycopene possesses antimetastatic activity in a highly invasive hepatoma SK-Hep-1 cell line, little is known whether its metabolites have a similar effect. In this study, we investigated the antimetastatic effects of apo-8'-lycopenal (1-10 µM) in comparison with lycopene (10 µM) in SK-Hep-1 cells. We found that both apo-8'-lycopenal and lycopene inhibited the invasion and migration of SK-Hep-1 cells, and the effect of apo-8'-lycopenal was stronger than that of lycopene at the same concentration (10 µM). Mechanistically, apo-8'-lycopenal: 1) decreased the activities and protein expression of metalloproteinase-2 (MMP-2) and -9; 2) increased the protein expression of nm23-H1 and the tissue inhibitor of MMP (TIMP)-1 and -2; 3) suppressed protein expression of Rho small GTPases; and 4) inhibited focal adhesion kinase-mediated signaling pathway, such as ERK/p38 and PI3K-Akt axis. Overall, these results demonstrate that apo-8'-lycopenal possesses antimetastatic activity in SK-Hep-1 cells and that this effect is stronger than that of lycopene, suggesting that the antimetastatic effect may be attributed, at least in part, to its metabolites such as apo-8'-lycopenal.