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  • Stability of dietary polyphenols: It's never too late to mend?
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-04-05
    Jianbo Xiao

    We have comprehensively investigated the structure-stability relationship of natural polyphenols in DMEM medium without cells. Polyphenols with catechol or pyrogallol structure were evidently instable in DMEM medium without cells. Herein, we further investigate stability of polyphenols when incubated with cancer cells and its related mechanism. After incubated with SK-28 cells and A549 cells at 37 °C in 5% CO2 for 72 h, the new products of quercetin and 5,7,3′,4′-tetrahydroxyflavone were found to quite different from different cells. It is time to investigate what really happened for polyphenols and the new products of polyphenols in cancer cells, as well as the related mechanism. It is very important to further check the bioactivity of these new products, which will avoid erroneous conclusions for what's the really bioactive compounds.

  • Effects of subchronic lead intoxication of rats on the myocardium contractility
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-20
    Yuri L. Protsenko, Boris A. Katsnelson, Svetlana V. Klinova, Oleg N. Lookin, Alexander A. Balakin, Larisa V. Nikitina, Leonid B. Katsnelson, Oksana P. Gerzen, Ilzira A. Minigalieva, Larisa I. Privalova, Vladimir B. Gurvich, Marina P. Sutunkova

    Outbred male rats were repeatedly injected IP with sub-lethal doses of lead acetate 3 times a week during 5 weeks. They developed an explicit, even if moderate, lead intoxication characterized by typical hematological and some other features. The next day after the last injection the heart of each animal was excised, and the trabecules and papillary muscles from the right ventricle were used for modeling in vitro isometric (with varying starting length of the preparation) regimes of the contraction-relaxation cycle with different preloads. Several well-established parameters of this model were found changed compared with the preparations taken from the hearts of healthy control rats. Background in vivo calcium treatment attenuated both systemic and cardiotoxic effects of lead to an extent. We show for the first time that subchronic intoxication with lead caused myocardial preparations in a wide range of lengths to respond by a decrease in the time and speed parameters of the isometric contraction while maintaining its amplitude and by a decrease in the passive stiffness of trabecules. The responses of the various heart structures are outlined, and the isomyosin ratio is shown to have shifted towards the slow isoform. Mechanistic and toxicological inferences from the results are discussed.

  • Detection of adulteration in Hydrastis canadensis (goldenseal) dietary supplements via untargeted mass spectrometry-based metabolomics
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-19
    Emily D. Wallace, Nicholas H. Oberlies, Nadja B. Cech, Joshua J. Kellogg

    Current estimates report that approximately 25% of U.S. adults use dietary supplements for medicinal purposes. Yet, regulation and transparency within the dietary supplement industry remains a challenge, and economic incentives encourage adulteration or augmentation of botanical dietary supplement products. Undisclosed changes to the dietary supplement composition could impact safety and efficacy; thus, there is a continued need to monitor possible botanical adulteration or mis-identification. Goldenseal, Hydrastis canadensis L. (Ranunculaceae), is a well-known botanical used to combat bacterial infections and digestive problems and is widely available as a dietary supplement. The goal of this study was to evaluate potential adulteration in commercial botanical products using untargeted metabolomics, with H. canadensis supplements serving as a test case. An untargeted ultraperformance liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis was performed on 35 H. canadensis commercial products. Visual inspection of the chemometric data via principal component analysis (PCA) revealed several products that were distinct from the main groupings of samples, and subsequent evaluation of contributing metabolites led to their confirmation of the outliers as originating from a non-goldenseal species or a mixture of plant materials. The obtained results demonstrate the potential for untargeted metabolomics to discriminate between multiple unknown products and predict possible adulteration.

  • Perfluorobutanesulfonic acid (PFBS) potentiates adipogenesis of 3T3-L1 adipocytes
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-18
    Weipeng Qi, John M. Clark, Alicia R. Timme-Laragy, Yeonhwa Park

    Perfluorobutanesulfonic acid (PFBS) is used as the replacement of perfluorooctanesulfonic acid (PFOS) since 2000 because of the concern on PFOS’ persistence in the environment and the bioaccumulation in animals. Accumulating evidence has shown the correlation between the exposure to perfluorinated compounds and enhanced adipogenesis. There is no report, however, of the effect of PFBS on adipogenesis. Therefore, the present work aimed to investigate the role of PFBS in adipogenesis using 3T3-L1 adipocytes. PFBS treatment for 6 days extensively promoted the differentiation of 3T3-L1 preadipocytes to adipocytes, resulting in significantly increased triglyceride levels. In particular, the treatments of PFBS at the early adipogenic differentiation period (day 0–2) were positively correlated with increased the triglyceride accumulation on day 6. PFBS treatments significantly increased the protein and mRNA levels of the master transcription factors in adipocyte differentiation; CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor gamma (PPARγ), along with acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), the key proteins in lipogenesis. PFBS significantly activated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) after 4-h treatment, and PFBS′ effect on triglyceride was abolished by U0126, a specific MAPK/ERK kinase (MEK) inhibitor. In conclusion, PFBS increased the adipogenesis of 3T3-L1 adipocytes, in part, via MEK/ERK-dependent pathway.

  • Antioxidant, anti-inflammatory and synergistic anti-hyperglycemic effects of Malaysian propolis and metformin in streptozotocin–induced diabetic rats
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-17
    Victor Udo Nna, Ainul Bahiyah Abu Bakar, Md Rizman, Md Lazin, Md Lazim, Mahaneem Mohamed

    Diabetes mellitus is characterized by hyperglycemia which causes oxidative stress. Propolis has been reported to have antihyperglycemic and antioxidant potentials. The present study therefore examined the anti-hyperglycemic, antioxidant and anti-inflammatory activities of Malaysian propolis (MP) using streptozotocin-induced diabetic rats. Ethanol extract of MP showed in vitro antioxidant (DPPH, FRAP and H2O2 radical scavenging) and α-glucosidase inhibition activities. Male Sprague Dawley rats were either treated with distilled water (normal control and diabetic control), MP (300 mg/kg b. w.), metformin (Met) (300 mg/kg b. w.) or both. After four weeks, fasting blood glucose decreased, while body weight change and serum insulin level increased significantly in MP, Met and MP + Met treated diabetic groups compared to diabetic control (DC) group. Furthermore, pancreatic antioxidant enzymes, total antioxidant capacity, interleukin (IL)-10 and proliferating cell nuclear antigen increased, while malondialdehyde, nuclear factor-kappa B (p65), tumor necrosis factor alpha, IL-1β and cleaved caspase-3 decreased significantly in the treated diabetic groups compared to DC group. Histopathology of the pancreas showed increased islet area and number of beta cells in the treated groups, compared to DC group, with D + MP + Met group comparable to normal control. We conclude that MP has anti-hyperglycemic, antioxidant, anti-inflammatory and antiapoptotic potentials, and exhibits synergistic effect with metformin.

  • In vitro systems toxicology-based assessment of the potential modified risk tobacco product CHTP 1.2 for vascular inflammation- and cytotoxicity-associated mechanisms promoting adhesion of monocytic cells to human coronary arterial endothelial cells
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-17
    Carine Poussin, Alexandra Laurent, Athanasios Kondylis, Diego Marescotti, Marco van der Toorn, Emmanuel Guedj, Didier Goedertier, Stefano Acali, Claudius Pak, Rémi Dulize, Karine Baumer, Dariusz Peric, Elodie Maluenda, David Bornand, Ignacio Gonzalez Suarez, Walter K. Schlage, Nikolai V. Ivanov, Manuel C. Peitsch, Julia Hoeng

    Cigarette smoking causes cardiovascular diseases. Heating tobacco instead of burning it reduces the amount of toxic compounds in the aerosol and may exert a reduced impact on health compared with cigarette smoke. Aqueous extract from the aerosol of a potential modified risk tobacco product, the Carbon Heated Tobacco Product (CHTP) 1.2, was compared in vitro with aqueous extract from the smoke of a 3R4F reference cigarette for its impact on the adhesion of monocytic cells to artery endothelial cells. Human coronary arterial endothelial cells (HCAEC) were treated for 4 h with conditioned media from monocytic Mono Mac 6 (MM6) cells exposed to CHTP1.2 or 3R4F extracts for 2 h or directly with those extracts freshly generated. In vitro monocyte-endothelial cell adhesion was measured concomitantly with inflammatory, oxidative stress, cytotoxicity, and death markers. Furthermore, transcriptomics analyses enabled to quantify the level of perturbation in HCAECs, and provide biological interpretation for the underlying molecular changes following exposure to 3R4F or CHTP1.2 extract. Our systems toxicology study demonstrated that approximately 10–15-fold higher concentrations of the CHTP 1.2 aerosol extract were needed to elicit similar effects as the 3R4F smoke extract on cardiovascular disease-relevant inflammation and cytotoxicity-related mechanisms and markers investigated in vitro.

  • Mercury concentrations in seafood and the associated risk in women with high fish consumption from coastal villages of Sonora, Mexico
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-17
    Jaqueline García-Hernández, María Isabel Ortega-Vélez, Alma Delia Contreras Paniagua, Daniela Aguilera-Márquez, German Leyva-García, Jorge Torre-Cosío

    Mercury concentrations in the ocean have increased considerably since the industrialrevolution and will continue to increase in the next 50 years. Therefore, it is important to monitor Hg levels in fish and to evaluate the health risks in populations with high fish consumption. In the present study, a total of 238 samples of commercial fish and shellfish, were analyzed from the Central Gulf of California, Mexico. Concentrations of total Hg in fish ranged from < DL (detection limit) up to 1.22 μg g-1, with a mean of 0.15 ± 0.19 μg g- 1, the majority of the samples were lower than the maximum permissible level. To evaluate the risk, a total of 110 food frequency questionnaires were applied to women (16–68 years old) from 15 coastal fishing villages of Sonora. Results indicated a high seafood consumption at these communities (mean = 307 g day-1), and a high hazard risk (HQ = 6.2) due to methyl mercury ingestion. It is recommended to limit seafood consumption in pregnant women to 4 portions of fish per week, preferably of low mercury concentrations so that all the benefits of seafood consumption are obtained without the negative health effects of methyl mercury.

  • Hepatoprotective effects of diosmin and/or sildenafil against cholestatic liver cirrhosis: The role of Keap-1/Nrf-2 and P38-MAPK/NF-κB/iNOS signaling pathway
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-17
    Fares E.M. Ali, Amany A. Azouz, Adel G. Bakr, Amira M. Abo-youssef, Ramadan A.M. Hemeida

    The present study was designed to investigate the potential protective effects of diosmin (DS) and/or sildenafil against bile duct ligation (BDL). In order to achieve this goal, BDL was performed to induce liver cirrhosis, DS (100 mg/kg/day, p.o.) and sildenafil (10 mg/kg, twice daily, p.o.) were administrated alone or in combination 24 h after the surgical operation and lasted for 4 weeks. Liver function biomarkers, fibrotic markers, oxidative stress markers, mRNA expression of NF-κB-p65, P38-MAPK, Nrf-2, and Keap-1, as well as protein expression of cytoglobin, NF-κB-p65, Nrf-2, iNOS and eNOS were investigated concomitantly with histopathological study. The results revealed that, 4 weeks of BDL induced a significant alteration in liver functions, fibrotic and oxidative stress markers. Furthermore, up-regulation of NF-κB-p65, P38-MAPK, Keap-1 and iNOS concomitantly with down-regulation of Nrf-2, cytoglobin and eNOS expressions were observed after BDL. DS and/or sildenafil treatment significantly alleviated the disturbance induced by BDL. These findings were further supported by the improvement in histopathological features. Additionally, co-administration of DS and sildenafil were found to significantly improved liver defects due to BDL as compared to the individual drugs. It can be concluded that, DS and sildenafil exhibit hepatoprotective effects through modulation of Keap-1/Nrf-2 and P38-MAPK/NF-κB/iNOS pathway.

  • Resveratrol inhibits human leiomyoma cell proliferation via crosstalk between integrin αvβ3 and IGF-1R
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-17
    Yih Ho, Yu-Chen Sh Yang, Yu-Tang Chin, Szu-Yi Chou, Yi-Ru Chen, Ya-Jung Shih, Jacqueline Whang-Peng, Chun A. Changou, Hsuan-Liang Liu, Shwu-Jiuan Lin, Heng-Yuan Tang, Hung-Yun Lin, Paul J. Davis

    Leiomyomas (myomas) are the most common benign smooth muscle cell tumor of the myometrium. Resveratrol, a stilbene, has been used as an anti-inflammatory and antitumor agent. In the current study, we investigated the inhibitory effect of resveratrol on the proliferation of primary human myoma cell cultures. Resveratrol arrested cell proliferation via integrin αvβ3. It also inhibited integrin αvβ3 expression and protein accumulation. Concurrently, constitutive AKT phosphorylation in myoma cells was inhibited by resveratrol. Expressions of proapoptotic genes, such as cyclooxygenase (COX)-2, p21 and CDKN2, were induced by resveratrol in myoma cells. On the other hand, expressions of proliferative (anti-apoptotic) genes were either inhibited, as in BCL2, or unchanged, as in cyclin D1 and proliferating cell nuclear antigen (PCNA). The accumulation of insulin-like growth factor (IGF)-1 receptor (IGF-1R) was inhibited by resveratrol in primary myoma cells. IGF-1-induced cell proliferation was inhibited by co-incubation with resveratrol. Therefore, growth modulation of myoma cells occurs via mechanisms dependent on cross-talk between integrin αvβ3 and IGF-1R. Our findings suggest that resveratrol can be considered an alternative therapeutic agent for myomas.

  • Detection of biogenic amines and microbial safety assessment of novel Meju fermented with addition of Nelumbo nucifera, Ginkgo biloba, and Allium sativum
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-04-10
    Shruti Shukla, Jong Suk Lee, Vivek K. Bajpai, Shivraj Hariram Nile, Yun Suk Huh, Young-Kyu Han, Myunghee Kim

    Meju, a cooked and fermented soy bean based food product, is used as a major ingredient in Korean traditional fermented foods such as Doenjang. We developed a novel type of Meju using single and combined extracts of Allium sativum (garlic clove), Nelumbo nucifera (lotus leaves), and Ginkgo biloba (ginkgo leaves) at 1% and 10% concentrations to improve the safety of Meju-based fermented products. Biogenic amines (BAs) in protein-rich fermented food products pose considerable toxical risks. The objective of this study was to investigate the effects of adding selected plant extracts in Meju samples during fermentation. Nine BAs, including tryptamine, 2-phenylethylamine, putrescine, cadaverine, agmatine, histamine, tyramine, spermidine and spermine, were isolated from Meju samples after sample derivatization with dansyl chloride and analyzed by high performance liquid chromatography. As a result, all tested Meju samples with added plant extracts showed total BAs levels in the range of 20.12 ± 2.03 to 118.42 ± 10.68 mg/100 g, which were below the safety limit set by various regulatory authorities (USFDA/KFDA/EFSA). However, among all tested Meju samples, LOM10 (Meju fermented with Nelumbo nucifera at 10% concentration) showed higher levels of BAs content than others either due to batch-to-batch variability or reduced beneficial microorganisms and/or due to increase in BA forming microorganisms. Also, none of the samples showed the aflatoxin level above the detection limit. Furthermore, all the tested Meju samples improved microbial safety as confirmed by the complete absence of Salmonella species and Staphylococcus aureus. However, some of the Meju samples showed the presence of coliforms (in range of 1.6 × 100–1.1 × 103 CFU/g), which is under regulatory limits. These results suggested that the use of plant extracts in Meju during fermentation have potential to improve microbial and toxicological safety of Meju products.

  • ZH-1 enhances the anticancer activity of gemcitabine via deoxyribonucleotide synthesis and apoptotic pathway against A549 cells
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-04-10
    Jianru Guo, Yan Li, Christopher Wai Kei Lam, Caiyun Wang, Meicun Yao, Wei Zhang

    The purpose of this study was to investigate the inhibitory effect of ZH-1 ((6S,9aS,6aR,9bR)-6-(phenylcarbonyl)-6,6a,9a,9b-tetrahydro-8H-azolidino[3,4-a]b enzo [e]indolizine-7,9-dione) and its potential interaction with gemcitabine in A549 cells. MTT assay showed that the combined use of gemcitabine and ZH-1 presented a significant inhibition effect on A549 cell growth with the cell viability from 82.3 ± 5.6% to 51.0 ± 6.6%. The CI value was 0.60 suggesting a synergistic effect between these two drugs. HPLC-MS/MS data indicated that combined treatment with gemcitabine and ZH-1 induced a significant decrease in deoxyadenosine triphosphate, deoxycytidine triphosphate, deoxyguanosine triphosphate and deoxythymidine triphosphate levels compared with use of gemcitabine alone. Five RNs as well as seven dRNs were considered to be significantly contributive to the discrimination of samples. Furthermore, western blot analysis revealed that the combination treatment caused A549 cell apoptosis via the intrinsic pathway by up-regulating Bax/Bcl-2 ratio, activating caspase-9, caspase-3 and poly-ADP-ribose polymerase, and promoting caspase-7, caspase-9 and poly-ADP-ribose polymerase cleavage. Collectively, the combined treatment with gemcitabine and ZH-1 exerted a strong synergistic action on anticancer activity through growth inhibition, perturbations in ribonucleotides and deoxyribonucleotides and the activation of intrinsic apoptotic signaling pathway.

  • Toxicological characteristics of edible insects in China: A historical review
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-04-10
    Yu Gao, Di Wang, Meng-Lei Xu, Shu-Sen Shi, Jin-Feng Xiong

    Edible insects are ideal food sources, which contain important nutrients and health-promoting compounds. With a rapid development of industrial insect farming, insect-derived food is a novel and emerging food industry. Edible insects have been traditionally consumed in various communities, while continuously gaining relevance in today's society; however, they currently remain underutilized. Although there are a large number of literature on edible insects, these literature primarily focus on the nutritional value edible insects. The toxicity assessment data of edible insects remain incomprehensive, especially for the new national standard that is currently in effect; and many data and conclusions are not accurately specified/reported. Therefore, we performed a literature review and summarized the data on the toxicological assessment of edible insects in China. The review first describes the research progress on safety toxicological assessment, and then offers references regarding the development of 34 edible insect species in China. These data can be a platform for the development of future toxicological assessment strategies, which can be carried out by a multidisciplinary team, possibly consisting of food engineers, agronomists, farmers, and so on, to improve the acceptability of edible insects.

  • Antitrypanosomal, antileishmanial and cytotoxic activities of Brazilian red propolis and plant resin of Dalbergia ecastaphyllum (L) Taub
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-04-14
    Marcos da Silveira Regueira-Neto, Saulo Relison Tintino, Miriam Rolón, Cathia Coronal, Maria C. Vega, Valdir de Queiroz Balbino, Henrique Douglas de Melo Coutinho

    The treatment for leishmaniasis and Chagas disease can be hard and painful, such that many patients give up on the treatment. In order to find an alternative path for the treatment of these diseases, researchers are using natural products to fight these parasites. The aim of this study was to evaluate the antiprotozoan and cytotoxic activities of red propolis samples collected from different Brazilian states and seasons whilst searching for possible activity differences. We also compared the red propolis results with the ones obtained for the plant resin extract collected from Dalbergia ecastaphyllum trees. The hydroethanolic red propolis extracts from Pernambuco and Alagoas, and the D. ecastaphyllum resin were evaluated regarding their antileishmanial, antitrypanosomal and cytotoxic activity. All extracts showed antiprotozoan and cytotoxic activity. RP-PER showed to be more cytotoxic against protozoan parasites and fibroblast cells. All propolis extracts showed a higher cytotoxic activity when compared to resin extracts. The propolis sample collected in Pernambuco during the rainy season killed the parasites with lower concentrations than the sample collected in the dry season. The IC50 observed against the parasites could be used without high fibroblast cell damage.

  • Regulation of cancer cell signaling pathways by mushrooms and their bioactive molecules: Overview of the journey from benchtop to clinical trials
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-04-19
    Aliye Aras, Sumbul Khalid, Saima Jabeen, Ammad Ahmad Farooqi, Baojun Xu

    Mushrooms represent a tremendous source of biologically useful and pharmacologically active molecules. Recent breakthroughs in cancer genetics, genomics, proteomics and translational research have helped us to develop a better understanding of the underlying mechanisms which are contributory in cancer development and progression. Different signaling pathways particularly, Wnt, SHH, TGF/SMAD and JAK/STAT have been shown to modulate cancer progression and development. Increasingly it is being realized that genetic/epigenetic mutations and loss of apoptosis also mandate a 'multi-molecular' perspective for the development of therapies to treat cancer. In this review we attempted to provide an overview of the regulation of different signaling pathways by mushrooms and their bioactive compounds. Regulation of Wnt and JAK-STAT pathways by mushrooms is deeply studied but we do not have comprehensive information about regulation of TGF/SMAD, Notch and TRAIL induced signaling pathways because of superficially available data. There are outstanding questions related to modulation of oncogenic and tumor suppressor microRNAs by mushrooms in different cancers. Therefore, detailed mechanistic insights related to targeting of multiple pathways by extracts or bioactive compounds from mushrooms will be helpful in bridging our current knowledge gaps and translation of medicinally precious bioactive molecules to clinically effective therapeutics.

  • HPLC profile and antiedematogenic activity of Ximenia americana L. (Olacaceae) in mice models of skin inflammation
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-04-20
    Bruno Anderson Fernandes da Silva, Roger Henrique Sousa da Costa, Cícera Norma Fernandes, Laura Hévila Inocêncio Leite, Jaime Ribeiro-Filho, Tatiana Rodrigues Garcia, Henrique Douglas Melo Coutinho, Almir Gonçalves Wanderley, Irwin Rose Alencar de Menezes

    The aim of this study was to evaluate the anti-edematogenic activity of X. americana L. (HEXA) hydroethanolic extract in ear edema models (acute and chronic) induced by croton oil and by different phlogistic agents (arachidonic acid, capsaicin, phenol and histamine), identifying the possible anti-edematogenic mechanism. HEXA demonstrated a significant anti-edematogenic effect at concentrations of 100–500 μg/ear in ear edema induced by croton oil with higher inhibition of edema of 39.37. However, the concentrations of 100 and 200 μg/ear were taken as a standard, demonstrating the effect in the chronic model induced by croton oil with inhibition of 61.62% and 48.74%. In the AA-induced ear edema model, HEXA showed inhibition of: 24.45% and 32.31%; capsaicin inhibition of 72.72% and 47.57%; phenol inhibition of 34% and 20.1%; and histamine inhibition of 31.8% and 21.62%. Then, the results were showed that HEXA demonstrated an anti-edematogenic effect in acute and chronic inflammation models, demonstrating a probable mechanism of action by the inhibition or modulation of key mediators of the inflammatory process. The chemical profile and presence of flavonoids guaranteeing a profile of activity similar to natural drugs that act or modulate the production of mediators of inflammations.

  • Development of novel techniques to extract phenolic compounds from Romanian cultivars of Prunus domestica L. and their biological properties
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-04-22
    Andrei Mocan, Alina Diuzheva, Simone Carradori, Vasil Andruch, Chiara Massafra, Cadmiel Moldovan, Cristian Sisea, Jacobus P. Petzer, Anél Petzer, Susi Zara, Guya Diletta Marconi, Gokhan Zengin, Gianina Crișan, Marcello Locatelli

    In the present work, fourteen cultivars of Prunus domestica were analysed to investigate their phenolic pattern with the purpose of using the leaves as potential resources of bioactive compounds in the pharmaceutical and food industry. Microwave-assisted extraction (MAE), dispersive liquid–liquid microextraction and sugaring-out liquid–liquid extraction techniques were optimized in order to obtain an exhaustive multi-component panel of phenolic compounds. The best phenolic-enriched recovery was achieved using MAE in water:methanol (30:70), and this procedure was further applied for quantitative analysis of phenolic compounds in real samples. In order to prove the safeness of these extracts, the biological potential of the Prunus cultivars was tested by several in vitro antioxidant and enzyme inhibitory assays. Moreover, their cytotoxicity was evaluated on human gingival fibroblasts (HGFs), and in most of the cases the treatment with different concentrations of extracts didn't show cytotoxicity up to 500 μg/mL. Only ‘Carpatin’ and ‘Minerva’ cultivars, at 250 and 500 μg/mL, reduced partially cell viability of HGFs population. Noteworthy, Centenar cultivar was the most active for the α-glucosidase inhibition (6.77 mmolACAE/g extract), whereas Ialomița cultivar showed the best antityrosinase activity (23.07 mgKAE/g extract). Overall, leaves of P. domestica represent a rich alternative source of bioactive compounds.

  • Zhiheshouwu ethanol extract induces intrinsic apoptosis and reduces unsaturated fatty acids via SREBP1 pathway in hepatocellular carcinoma cells
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-04-24
    Hongliang Li, Longchao Xiang, Nian Yang, Fengjun Cao, Chen Li, Ping Chen, Xuzhi Ruan, Yibin Feng, Nian Zhou, Xuanbin Wang

    Hepatocellular carcinoma (HCC) is the major incidence and one of the most life-threatening cancer. How to conquer HCC is a worldwide issue for patients. Zhiheshouwu (Polygoni multiflori Radix Praeparata) is a Chinese medicinal herb exhibiting both lowering lipid and inhibiting cancer cells. However, it remains a matter if its inhibiting cancer cells is related to its lowering lipid. In this study, we investigate the effects of Zhiheshouwu ethanolic extract (HSWE) on apoptosis and the underlying mechanisms in Bel-7402 cells. The results showed that HSWE inhibited the proliferation with an increased level of ALT and AST in Bel-7402 cells. The decreased mitochondrial membrane potential (ΔΨm) was observed in HSWE-treated Bel-7402 cells. The flow cytometry results showed that HSWE triggered apoptosis. Since mitochondrial injury is characterized as intrinsic apoptotic cell death, these data indicated that HSWE may induce intrinsic apoptosis in Bel-7402 cells. In addition, HSWE decreased the production of unsaturated fatty acids, and inhibited the mRNA and protein of SCD1 and its up-stream factor, sterol-regulatory element binding proteins 1 (SREBP1), a master transcriptional regulator of lipogenic gene. Taken together, these data suggest that HSWE induces an intrinsic apoptosis, and reduced unsaturated fatty acids by blocking SREBP1 in hepatocellular carcinoma cells.

  • Current standing of plant derived flavonoids as an antidepressant
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-04-25
    Haroon Khan, Sadia Perviz, Antoni Sureda, Seyed M. Nabavi, Silvia Tejada

    Depression, a multifactorial brain disorder, is one of the most prevalent diseases worldwide. Several strategies have been developed to counteract the main symptoms and disorders. However, the treatments are usually associated with different side effects or poor effect. For that reason, new necessary approaches are emerging; among them, natural products are good alternatives since no interactions have been described up to now. Flavonoids have been related to antidepressant effects in cell lines and animal models by their action on the amine mechanisms protecting the neuroendocrine and immune systems. The current review includes an approach of some of the main results related to the action of flavonoids on depression found in the literature and a short view of the possible mechanisms involved. Thus, it highlights the potential emerging candidates with strong antidepressant effects which could be effective new compounds.

  • Di (2-ethylhexyl) phthalate (DEHP)-induced hepatotoxicity in quails (Coturnix japonica) via triggering nuclear xenobiotic receptors and modulating cytochrome P450 systems
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-11
    Ying-Zhi Zhang, Yu-Zhu Zuo, Zheng-Hai Du, Jun Xia, Cong Zhang, Hui Wang, Xue-Nan Li, Jin-Long Li

    Di (2-ethylhexyl) phthalate (DEHP) is a widely distributed pollutant that is of great concern due to its negative health effects. However, whether DEHP exposure causes liver toxicity in birds remains unclear. To clarify the potential hepatotoxicity of DEHP, quails were exposed to 0, 250, 500 and 1000 mg/kg BW/day DEHP by gavage treatment for 45 days. The livers of DEHP-exposed quails showed histomorphological changes. DEHP exposure induced a significant increase in cytochrome P450 enzyme system (CYP450s) activity (including aniline-4-hydroxylase (AH), aminopyrine N-demethylase (APND), erythromycin N-demethylase (ERND) and NADPH-cytochrome C reductase (NCR)) and in the contents of total cytochrome P450 (CYP450) and cytochrome b5 (Cyt b5) in quail liver. DEHP exposure also influenced the expression of nuclear xenobiotic receptors (NXRs) and CYP450 isoforms in the liver. The results suggested that DEHP-induced hepatotoxicity in quail liver is associated with activation of the NXRs pathway responses and disruption of CYP450s homeostasis. This study will help to further elucidate DEHP exposure-induced liver toxicity in quails.

  • Are wild and cultivated flowers served in restaurants or sold by local producers in Denmark safe for the consumer?
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-05
    Mikael M. Egebjerg, Pelle T. Olesen, Folmer D. Eriksen, Gitte Ravn-Haren, Lea Bredsdorff, Kirsten Pilegaar

    New Nordic Food has within the last decade received much media coverage with chefs of top restaurants using wild plants for foods. As part of a control campaign, the Danish Veterinary and Food Administration visited 150 restaurants and local food producers from May-October 2016 and investigated their use of plants picked from the wild, cultivated in private gardens or market gardens. Among the species used were the flowers from 23 plants. Here we present a safety evaluation of these flowers based on published phytochemical investigations and toxicological data in humans, farm animals, pets, or experimental animals. Of the 23 flowers reviewed, nine contained compounds with toxic or potentially toxic effects if eaten, two contained unidentified toxic compound(s), and four were flowers from plants with potentially toxic compounds present in other plant parts or related species. Many of the flowers may be considered novel, since a use to a significant degree in Europe prior to 15 May 1997 before Regulation (EC) 258/97 on novel food and novel food ingredients came into force could not be established. In conclusion, this review illuminates a striking lack of chemical and toxicological data of many of the proposed wild or cultivated flowers for food use.

  • Targeting ERK signaling pathway by polyphenols as novel therapeutic strategy for neurodegeneration
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-05
    Mohammad Hosein Farzaei, Devesh Tewari, Saeideh Momtaz, Sandro Argüelles, Seyed Mohammad Nabavi

    Numerous chemicals, such as phenolic compounds are strong radical scavengers, capable of alleviating oxidative stress associated neurodegeneration. Dietary antioxidants, especially flavonoids, are being considered as a promising approach to prevent or slow the pathological development of neurological illness and aging. One of the major advantage of natural products is that of their anti-amyloid effects over synthetic counterpart, however a healthy diet provides these beneficial natural substances as nutraceuticals. The extracellular-signal-regulated kinase (ERK) is one of the main pharmacological target of natural phenolic compounds, which involves in several therapeutic effects. Mounting evidence revealed that numerous bioflavonoids, obtained from a variety of dietary fruits or plants as well as medicinal herbal sources, exhibit protective or therapeutic functions versus development of neurodegenerative diseases mainly through modulation of different compartments of ERK signaling pathway. Currently, there is remarkable interest in the beneficial effects of natural flavonoids to improve neural performance and prevent the onset and development of major neurodegenerative diseases. Natural products originated from medicinal plants, in particular antioxidants, have gained a great deal of attention due to their safe and non-toxic natures. Here, we summarized the effect of natural bioflavonoids on ERK signaling pathway and their molecular mechanism.

  • Protective effects of (-)-epicatechin and the colonic metabolite 3,4-dihydroxyphenylacetic acid against glucotoxicity-induced insulin signalling blockade and altered glucose uptake and production in renal tubular NRK-52E cells
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-06
    David Álvarez-Cilleros, María Ángeles Martín, Sonia Ramos

    Glucotoxicity (high levels of glucose) is a major cause in the pathogenesis of diabetes. Evidences indicate that (-)-epicatechin (EC) and colonic metabolites derived from flavonoid intake could possess antidiabetic effects, but the mechanisms for their preventive activities related to glucose homeostasis and insulin signalling in the kidney remain largely unknown. This work is aimed to investigate the effect of EC and main colonic phenolic acids derived from flavonoid intake, i.e. 2,3-dihydroxybenzoic-acid, 3,4-dihydroxyphenylacetic-acid (DHPAA) and 3-hydroxyphenylpropionic-acid, on insulin signalling, and glucose production and uptake in renal tubular proximal NRK-52E cells treated with high glucose. Pre-treatment with EC or DHPAA prevented the decreased tyrosine-phosphorylated and total levels of IR caused by high glucose. EC and DHPAA pre-treatment also avoided the inactivation of the PI3K/AKT pathway and AMPK, and the elevation of PEPCK levels induced by high glucose. Additionally, EC and DHPAA pre-treatment alleviated the altered glucose uptake and production caused by high glucose, although this protective effect was abrogated when AKT and AMPK were inhibited. These results suggest EC and DHPAA prevent or delay a potential dysfunction of NRK-52E cells treated with high glucose through the attenuation of the insulin signalling blockade and the modulation of glucose homeostasis via AKT and AMPK.

  • Investigations into the therapeutic potential of Asphodeline liburnica roots: In vitro and in silico biochemical and toxicological perspectives
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-06
    Marcello Locatelli, Serife Yerlikaya, Mehmet Cengiz Baloglu, Gokhan Zengin, Yasemin Celik Altunoglu, Francesco Cacciagrano, Cristina Campestre, Mohamad Fawzi Mahomoodally, Adriano Mollica

    This study aims to establish the biological and chemical profile of Asphodeline liburnica (Scop.) Rchb. root. The antioxidant, antimicrobial, enzyme inhibitory, DNA protection, apoptotic DNA ladder fragmentation analysis, and anti-proliferative of A. liburnica were established using standard assays. In silico study was also performed to understand interactions between quantified anthraquinones and key enzymes of clinical relevance. Total phenolic and flavonoid contents were found to be 9.67 mgGAE/g and 1.48 mgRE/g extract, respectively. Chrysophanol was detected as a major anthraquinone. The extract exhibited radical scavenging ability against DPPH and ABTS with values of 13.23 and 66.99 mgTE/g extract, respectively. Good inhibitory activity against tyrosinase was recorded. In silico experiments showed that the anthraquinones were able to establish coordinative bonds with the copper atoms present in the enzymatic cavity of tyrosinase. MTT cell viability test on MDA-MB-231 cells showed that at 0.1 and 1 μg of extracts induced anti-proliferative effect. Apoptotic DNA fragmentation analysis indicated nuclear condensation resulting in DNA fragmentation, which exhibited apoptotic cell death in the presence of A. liburnica. This study has provided insights on the potential usage of A. liburnica which could open new avenues for research and stimulate future interest for the development of safe novel biopharmaceuticals.

  • Bioaccessibility and decomposition of cylindrospermopsin in vegetables matrices after the application of an in vitro digestion model
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-06
    Sara Maisanaba, Remedios Guzmán-Guillén, Rocío Valderrama, Giuseppe Meca, Guillermina Font, Ángeles Jos, Ana M. Cameán

    Research on the human exposure to Cylindrospermopsin (CYN) via consumption of contaminated food is of great interest for risk assessment purposes. The aim of this work is to evaluate for the first time the CYN bioaccessibility in contaminated vegetables (uncooked lettuce and spinach, and boiled spinach) after an in vitro digestion model, including the salivar, gastric and duodenal phases and, colonic fermentation under lactic acid bacteria. The results obtained showed that the digestion processes are able to diminish CYN levels, mainly in the colonic phase, especially in combination with the boiling treatment, decreasing CYN levels in a significant way. Moreover, the potential decomposition products in a pure CYN solution and in CYN-contaminated vegetables were evaluated using UHPLC-MS/MS Orbitrap. Under the conditions assayed, only two diastereoisomers of the same fragment with m/z 292.09617 have been detected in all the analysed samples, with the exception of digested vegetables. Therefore, in terms of risk assessment, the digestion seems to play an important role in reducing the final bioaccesibility of CYN, and the consumption of cooked vegetables (spinach) would be safer in comparison to raw vegetables.

  • Molecular mechanism and inhibitory targets of dioscin in HepG2 cells
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-07
    Ying-Shuo Zhang, Yi-Long Ma, Kiran Thakur, Sayed Sajid Hussain, Jun Wang, Qi Zhang, Jian-Guo Zhang, Zhao-Jun Wei

    Dioscin has been known for its anti-cancer activity; however, its detailed molecular mechanisms have not been studied so far. Herein, we evaluated the anti-cancer activity of dioscin for proliferation inhibition and apoptosis in HepG2 cancer cells. Initially, dioscin was purified and identified from Polygonatum sibiricum by HPLC, MS, and NMR analysis, respectively. Dioscin inhibited the cell multiplication at IC50 of 8.34 μM, altered the cell morphology, arrested the cell cycle in G2/M phase and led to considerable programmed cell death. Furthermore, it has efficiently promoted the mitochondrial pathway and death receptor pathway. The inhibition of Caspase-8 and Caspase-9 proteins in these pathways abolished the dioscin induced apoptosis significantly; while dioscin inhibited the PI3K/Akt/mTOR pathway. Moreover, dioscin exposure led to enhanced intracellular ROS generation and the mRNA expression of JNK gene which emphasized their involvement in the apoptosis process in HepG2 cells.

  • Advances in drug-induced cholestasis: Clinical perspectives, potential mechanisms and in vitro systems
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-07
    M. Leonor Fernández-Murga, Petar D. Petrov, Isabel Conde, Jose V. Castell, M. José Goméz-Lechón, Ramiro Jover

    Despite growing research, drug-induced liver injury (DILI) remains a serious issue of increasing importance to the medical community that challenges health systems, pharmaceutical industries and drug regulatory agencies. Drug-induced cholestasis (DIC) represents a frequent manifestation of DILI in humans, which is characterised by an impaired canalicular bile flow resulting in a detrimental accumulation of bile constituents in blood and tissues. From a clinical point of view, cholestatic DILI generates a wide spectrum of presentations and can be a diagnostic challenge. The drug classes mostly associated with DIC are anti-infectious, anti-diabetic, anti-inflammatory, psychotropic and cardiovascular agents, steroids, and other miscellaneous drugs. The molecular mechanisms of DIC have been investigated since the 1980s but they remain debatable. It is recognised that altered expression and/or function of hepatobiliary membrane transporters underlies some forms of cholestasis, and this and other concomitant mechanisms are very likely in DIC. Deciphering these processes may pave the ways for diagnosis, prognosis and prevention, for which currently major gaps and caveats exist. In this review, we summarise recent advances in the field of DIC, including clinical aspects, the potential mechanisms postulated so far and the in vitro systems that can be useful to investigate and identify new cholestatic drugs.

  • Role of food-derived antioxidants against cisplatin induced-nephrotoxicity
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-07
    Tania Gómez-Sierra, Dianelena Eugenio-Pérez, Argelia Sánchez-Chinchillas, José Pedraza-Chaverri

    Cancer is a relevant public health problem, that represents the second leading cause of death. In this regard, cisplatin is a highly effective antineoplastic drug used in treatment of several types of cancer, such as head and neck, testicular, ovarian, gastric, lung and breast cancer. Nevertheless, treatment with this compound leads to nephrotoxicity, which limits its use. Oxidative stress plays a pivotal role in cisplatin-induced renal damage and several dietary antioxidants have been reported to ameliorate this secondary effect. Relevant findings on the protective effects of these antioxidant agents in cisplatin-induced nephrotoxicity are summarized in this paper. Further, limitations of animal models used in these studies are discussed. Additionally, clinical studies on the protective effect of these antioxidants, as well as future directions for these kind of trials are also considered.

  • Vasomotor dysfunction in human subcutaneous arteries exposed ex vivo to food-grade titanium dioxide
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-07
    Ditte Marie Jensen, Gry Freja Skovsted, Jens Lykkesfeldt, Rasmus Dreier, Jais Oliver Berg, Jørgen Lykke Jeppesen, Majid Sheykhzade, Steffen Loft, Peter Møller

    Animal studies have shown that titanium dioxide (TiO2) exposure affects arterial vasomotor function, whereas little is known about the effects in arteries from humans. This study investigated vasomotor responses after direct exposure of human subcutaneous arteries to food-grade TiO2 (E171) (14 or 140 μg/ml) for 30 min and 18 h. Vasomotor responses to bradykinin, 5-hydroxytryptamine (5-HT), sarafotoxin 6c (S6c) and nitroglycerin were recorded in wire-myographs. Vasoconstrictor responses to 5-HT were increased in arteries exposed to E171 for 18 h (P < 0.05). Furthermore, an increase in S6c responses was seen in low concentration E171 exposed arteries (30 min exposure; P < 0.05). The vasorelaxation response to nitroglycerin was increased in low concentration E171 exposed arteries (30 min exposure; P < 0.05). Arterial responses to bradykinin were unaffected after treatment with E171. There was no difference in gene expression levels of intercellular cell adhesion molecule 1, vascular cell adhesion molecule 1, 5-hydroxytryptamine receptor 1B, 5-hydroxytryptamine receptor 2A, endothelin receptor A and endothelin receptor B in E171 exposed arteries after exposure to TiO2 for 30 min or 18 h. In conclusion, this study shows that the same type of vasomotor dysfunction is found in artery segments of rats and humans following ex vivo exposure to E171.

  • Usnic acid reactive metabolites formation in human, rat, and mice microsomes. Implication for hepatotoxicity
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-04
    Kamil Piska, Agnieszka Galanty, Paulina Koczurkiewicz, Paweł Żmudzki, Joanna Potaczek, Irma Podolak, Elżbieta Pękala

    Usnic acid is a lichen compound which is extensively studied due to its cytotoxic, antiproliferative, antimicrobial, antiviral, antiprotozoal, and anti-inflammatory activities. Despite a broad spectrum of biological properties, usnic acid is a hepatotoxic agent, thus its potential use as a drug is limited. Certain hepatotoxic drugs may act by generating reactive metabolites that damage the liver. The aim of the study was to predict the biotransformation of usnic acid enantiomers to reactive products using a trapping assay with glutathione in human, rat, and mice liver microsomes. Our results indicate that each enantiomer forms two reactive metabolites; in turn, these metabolites form adducts with glutathione, which may partially explain the toxicity of usnic acid. In silico analysis indicated structural alerts for the generation of reactive metabolites in usnic acid formula. This study proposes a novel mode of the hepatic toxicity of usnic acid enantiomers; it also provides some useful suggestions for designing safer usnic acid derivatives.

  • Sulfanilic acid increases intracellular free-calcium concentration, induces reactive oxygen species production and impairs trypsin secretion in pancreatic AR42J cells
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-03
    Fatma Zohra Ameur, Nabila Mehedi, Omar Kheroua, Djamel Saïdi, Gines M. Salido, Antonio Gonzalez

    We studied the effects of the tartrazine-metabolite sulfanilic acid on the physiology of pancreatic AR42J cells. Sulfanilic acid (1 μM-1 mM) induced a slow and progressive increase in intracellular free-calcium concentration that reached a plateau. The effect of sulfanilic acid was not concentration-dependent. Stimulation of cells with thapsigargin (1 μM) after treatment with sulfanilic acid (1 mM) induced a smaller Ca2+ response compared with that obtained with thapsigargin alone. Sulfanilic acid induced a concentration-dependent production of reactive oxygen species; however, this effect was not Ca2+-dependent. Depolarization of mitochondrial membrane potential was observed at the concentration of 1 mM sulfanilic acid. In the presence of the compound a decrease in the GSH/GSSG ratio was observed. A decrease in the expression of superoxide dismutase 2 was noted. Finally, stimulation of cells with CCK-8 led to a concentration-dependent increase of trypsin secretion that was impaired by pretreatment of cells with sulfanilic acid. Preincubation of cells with the antioxidant melatonin (100 μM) reduced the effect of sulfanilic acid on trypsin secretion. We conclude that sulfanilic acid might induce oxidative stress, which could alter Ca2+ signaling and enzyme secretion in pancreatic AR42J cells. This creates a situation potentially leading to damage of the exocrine pancreas.

  • The concentration and probabilistic health risk assessment of pesticide residues in commercially available olive oils in Iran
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-03
    Najmeh Razzaghi, Parisa Ziarati, Hossein Rastegar, Shahram Shoeibi, Maryam Amirahmadi, Gea Oliveri Conti, Margherita Ferrante, Yadolah Fakhri, Amin Mousavi Khanghah

    This study was undertaken to analyze 29 pesticides residues in 37 commercially olive oil collected samples from Iran's markets using Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) approach along with acetonitrile for the extraction, surface adsorbents for clean-up procedure, following with a gas chromatography-mass spectroscopy (GC-MS). In order to eliminate the matrix effect, the calibration curves were drawn using spiked samples with the Area under curve (AUC) portion calculation of pesticide residue to AUC internal standard (Triphenyl Methane (TPM)). Moreover, the probabilistic health risk assessment includes non-carcinogenic and carcinogenic risk were estimated by target hazard quotient (THQ), total target hazard quotient (TTHQ) and cancer risk (CR) using the Monte Carlo Simulation (MCS) method. The calibration curves were linear in the range of 10–1500 ng/g, and R2 was higher than 0.994. All pesticides recoveries as average were in the range of 77.97–112.65%. The respective numbers attributed to LOD and LOQ were 3–5 ng/g and 8–15 ng/g. Results showed that 29.7% of samples were contaminated by pesticides which according to Iranian regulation, while in 7 cases banned pesticides were detected. Only 4 samples are noncompliant with EU regulation. The rank order of pesticides based on THQ was Heptachlor > DDT > Pretilachlor. Also, TTHQ for adults was 0.139; and children 0.467. The rank order of pesticides based on CR was Heptachlor > DDT. Consumers (adults and children) are not at non-carcinogenic risk due to ingestion of oil olive content (THQ and TTHQ < 1 value) but are at considerable carcinogenic (CR > 1E-6). According to the observed profile of pesticide in olive oil samples, which are mostly banned according to Iranian regulation, further improvements in agriculture procedures of cultivated olive in Iran, as well as required assessments of imported olive oil, was recommended.

  • Absence of renal adverse effects from β-myrcene dietary administration in OECD guideline-compliant subchronic toxicity study
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-07-04
    Maria Bastaki, Michel Aubanel, Mark Bauter, Thierry Cachet, Jan Demyttenaere, Maodo Malick Diop, Christie L. Harman, Shim-mo Hayashi, Gerhard Krammer, Xiaodong Li, Craig Llewellyn, Odete Mendes, Kevin J. Renskers, Jürgen Schnabel, Benjamin P.C. Smith, Sean V. Taylor

    β-Myrcene is a flavoring substance that occurs naturally in a large variety of foods. At the request of the European Food Safety Authority (EFSA) for additional toxicological data on β-myrcene, groups of Sprague Dawley rats (10/sex/group) were administered diets containing 0, 700, 2100, or 4200 ppm of β-myrcene designed to provide nominal doses of 0, 50, 150, or 300 mg/kg bw/day in a 90-day GLP-compliant study. Based on body weights, feed consumption, and substance stability data, final estimated daily intakes of β-myrcene were calculated to be 20.4, 58.8, and 115.2 mg/kg bw for males and 24.2, 70.0, and 135.9 mg/kg bw for females. No effects on clinical observations, hematology and clinical chemistry parameters, organ weights, or macroscopic and histopathological examinations were found attributable to ingestion of β-myrcene. The oral no-observed-adverse-effect level (NOAEL) for rats of both sexes was the highest dose tested. Based on feed consumption and test substance stability in the diet, the NOAEL was calculated to be 115 and 136 mg/kg bw/day for males and females, respectively.

  • A transcriptomic analysis of black cohosh: Actein alters cholesterol biosynthesis pathways and synergizes with simvastatin
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-30
    Linda Saxe Einbond, Morando Soffritti, Davide Degli Esposti, Hsan-au Wu, Michael Balick, Hongbao Ma, Stephen Redenti, Alan Roter
  • 更新日期:2018-07-01
  • In vitro and in vivo genotoxicity assessment of gold nanoparticles of different sizes comet and SMART assays
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-28
    A. Ávalos, A.I. Haza, D. Mateo, P. Morales

    Due to the increasing use of gold nanoparticles (AuNPs) in different areas such as medicine, biotechnology or food sector, human exposure to them has grown significantly and its toxicity evaluation has become essential. Therefore, the purpose of this study was to compare the potential genotoxic effects of 30, 50 and 90 nm AuNPs, using in vitro comet assay with the in vivo mutagenic and recombinogenic activity (SMART Test) in Drosophila. The results indicated that in both cell lines, 30, 50 and 90 nm (1–10 μg ml−1) AuNPs increased DNA strand breaks following 24 h treatment. This damage was not dose and size-dependent. Moreover, a modified comet assay using endonuclease III and formamidopyrimidine-DNA glycosylase restriction enzymes showed that in both cell lines, pyrimidines and purines were oxidatively damaged by all AuNPs, being 90 nm AuNPs slightly more genotoxic. However, the data obtained with SMART showed that 30 nm AuNPs did not modify the spontaneous frequencies of spots indicating lack of mutagenic and recombinogenic activity. Therefore, further experiments must be carried out to gain a better understanding of the mechanism of action of AuNPs to ensure their safe use.

  • Mechanism of cyclosporine A nephrotoxicity: Oxidative stress, autophagy, and signalings
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-28
    Qinghua Wu, Xu Wang, Eugenie Nepovimova, Yun Wang, Hualin Yang, Kamil Kuca

    Cyclosporine A (CsA) is a widely used immunosuppressive agent that greatly reduces the rates of kidney-, heart-, and liver-transplant rejection. However, CsA nephrotoxicity is a serious side effect that limits the clinical use of CsA. While the mechanisms underlying CsA nephrotoxicity are still not fully understood, increasing lines of evidence suggest that oxidative stress plays an important role in this phenomenon. Specifically, CsA induces endoplasmic reticulum stress and increases mitochondrial reactive oxygen species production: this modifies the redox balance, which causes lipid peroxidation and thereby induces nephrotoxicity. Recent studies on the pathogenesis of CsA nephrotoxicity suggest that CsA-induced autophagy can alleviate the deleterious effects of CsA-induced endoplasmic reticulum stress, thereby preventing nephrotoxicant-induced renal injury. A variety of signaling pathways participate in the pathogenesis of CsA nephrotoxicity. Specifically, the p38, ERK, and JNK MAPK subfamilies are all involved in CsA nephrotoxicity, while NF-κB is a target molecule of CsA. Moreover, the fibrogenic cytokine TGF-β1 contributes to CsA-induced renal fibrosis, while Nrf2 modulates CsA-induced cellular oxidative stress. In addition, CsA generally inhibits nitric oxide synthesis and impairs endothelium-dependent relaxation in the renal artery. However, some reports also suggest that nitric oxide synthesis is enhanced in the kidney cortex during CsA nephrotoxicity. Notably, the biomarkers of CsA nephrotoxicity associated with CsA have not been reviewed previously. Therefore, in this review, we will first provide an update on CsA nephrotoxicity in humans and describe the potential biomarkers of CsA nephrotoxicity. The molecular and cellular mechanisms that underlie CsA nephrotoxicity and the roles played by oxidative stress, autophagy, and signaling pathways will then be comprehensively summarized and discussed. Finally, the current therapeutical strategies for CsA nephrotoxcixity are summarized. We hope this review will provide a better understanding of CsA nephrotoxicity, thereby improving the management of patients who are treated with CsA.

  • Anti-proliferative activity-guided isolation of clerodermic acid from Salvia nemorosa L.: Geno/cytotoxicity and hypoxia-mediated mechanism of action
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-28
    Mir Babak Bahadori, Morteza Eskandani, Maria de Mieri, Matthias Hamburger, Hossein Nazemiyeh

    The adaptation of solid tumors to the low oxygen/nutrient environment is mediated by the pivotal transcription role of hypoxia inducible factor-1 (HIF-1). Thus, the HIF-1 and its subunits have been considered to be hopeful anti-cancer targets. Various natural compounds were reported to persuade cell cytotoxicity through targeting and downregulation the HIF-1. The genus Salvia is a rich source of bioactive terpenoids which show promising anti-cancer activities. Here, the identification of natural anti-proliferative compound targeting the HIF-1α expression was reported. A bioassay-guided isolation was employed for the discovery of natural anti-proliferative compounds from 12 Salvia extracts using MTT assay against A549 cells. In this direction, clerodermic acid (CDA) as a potent cytotoxic compound was purified from Salvia nemorosa and identified using 1D and 2D NMR analysis. Results indicated that CDA has anti-proliferation activity (IC50 value of 35 μg/mL) which was confirmed by genotoxicity and apoptosis detection analyses. The quantitative qPCR analysis showed that the expression level of HIF-1 alpha was strongly inhibited in the hypoxic cells treated with CDA compared to the untreated cells tolerated hypoxia. Findings exhibited that S. nemorosa and clerodermic acid have significant potential for reducing HIF-1α expression and could be considered for further studies for cancer therapy.

  • Nano-diamino-tetrac (NDAT) inhibits PD-L1 expression which is essential for proliferation in oral cancer cells
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-28
    Shan-Jen Lin, Yu-Tang Chin, Yih Ho, Szu-Yi Chou, Yu-Chen Sh Yang, André Wendindondé Nana, Kuan-Wei Su, Yee-Tong Lim, Kuan Wang, Sheng‐Yang Lee, Ya-Jung Shih, Yi-Ru Chen, Jacqueline Whang-Peng, Paul J. Davis, Hung-Yun Lin, Earl Fu

    Programmed death-ligand 1 (PD-L1) is a critical regulator to defend tumor cells against immune surveillance. Thyroid hormone has been shown to induce PD-L1 expression in cancer cells. Its nano-particulated analogue, nano-diamino-tetrac (NDAT; Nanotetrac) is an anticancer/anti-angiogenic agent. In the current study, the inhibitory mechanism by which NDAT inhibited PD-L1 mRNA abundance and PD-L1 protein content in oral cancer cells was investigated. NDAT inhibited inducible PD-L1 expression and protein accumulation by the inhibition of activated ERK1/2 and PI3K. Knockdown PD-L1 also inhibited the proliferation of oral cancer cells which suggests that the inhibitory effect of NDAT on PD-L1 expression maybe is one of the critical mechanisms for NDAT-induced anti-proliferative effect in oral cancer cells.

  • 更新日期:2018-06-27
  • Residue analysis and dietary exposure risk assessment of tebufenozide in stem lettuce (Lactuca sativa L. var. angustana Irish)
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-26
    Hongfang Lin, Xinze Liu, Yecheng Ma, Kyongjin Pang, Jiye Hu

    Tebufenozide, a newly-developed nonsteroidal ecdysone agonist, is in pre-regulation phase (before approval for use) on stem lettuce in China. Aiming at the safe application of tebufenozide, the dissipation and terminal residue trials on stem lettuce were performed under good agricultural practice (GAP). The dissipation trials shown that tebufenozide was rapidly degraded in stem lettuce, with half-lives of 5.0–8.2 days. Pre-regulation dietary exposure risk assessments were evaluated to recommend maximum residue limits (MRLs) based on risk quotients (RQ) method. Relevant toxicological parameters including ADI (acceptable daily intake) and ARfD (acute reference dose) were applied to assess the potential dietary exposure risk. The results indicated the chronic dietary exposure risk probability (RQc) of tebufenozide ranged from 36.4% to 70.0%. The acute dietary exposure risk probability (RQa) of tebufenozide was 2.88%–8.49% in lettuce stems and 14.0%–20.0% in lettuce leaves, respectively. On the basis of supervised field trial data and dietary exposure risk assessment results, the MRLs of tebufenozide were recommended as 3 mg/kg for lettuce stems and 10 mg/kg for lettuce leaves, respectively. The results demonstrated that the dietary exposure risk of tebufenozide used in stem lettuce under GAP was negligible and would not pose unacceptable health risk to Chinese consumers.

  • Absence of adverse effects following administration of piperine in the diet of Sprague-Dawley rats for 90 days ☆
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-26
    Maria Bastaki, Michel Aubanel, Mark Bauter, Thierry Cachet, Jan Demyttenaere, Maodo Malick Diop, Christie L. Harman, Shim-mo Hayashi, Gerhard Krammer, Xiaodong Li, Craig Llewellyn, Odete Mendes, Kevin J. Renskers, Jürgen Schnabel, Benjamin P.C. Smith, Sean V. Taylor

    Piperine (E,E-) is a naturally occurring pungent and spicy constituent of black pepperand is also used as an added flavoring ingredient to foods and beverages. Piperine has been determined safe under conditions of intended use as a flavoring substance by regulatory and scientific expert bodies. While concurring with the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and Flavor and Extract Manufacturers Association (FEMA) Expert Panel on the safety of piperine, the European Food Safety Authority (EFSA) requested additional toxicological data. The results of a 90-day GLPcompliant dietary study, conducted in Sprague-Dawley rats at target doses of 0, 5, 15, or 50 mg/kg bw/day, to respond to this request are presented herein. No adverse effects were found attributable to ingestion of piperine. Statistically significant changes in food consumption, body weight gain, and plasma cholesterol levels were not considered adverse as discussed in this paper. Therefore, the oral no-observed-adverse-effect level (NOAEL) was determined to be the highest dose tested of 50 mg/kg bw/day. EFSA derived a lower NOAEL of 5 mg/kg bw/day based on increased plasma cholesterol levels which still affords an adequate margin of safety of over 48,000 and concluded that piperine is not of safety concern.

  • The role of cholesterol oxidation products in food toxicity
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-27
    Lisaura Maldonado-Pereira, Matthew Schweiss, Carlo Barnaba, Ilce Gabriela Medina-Meza
  • Arsenic-induced apoptosis in the p53-proficient and p53-deficient cells through differential modulation of NFkB pathway
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-23
    Lei Yin, Xiaozhong Yu

    Arsenic is a well-known environmental carcinogen and an effective chemotherapeutic agent. The underlying mechanism of this dual-effect, however, is not fully understood. In this study, we applied mouse p53+/+ and p53−/− cells to examine the NFκB pathway and proinflammatory cytokines after arsenic treatment. Arsenic reduced cell viability and increased more apoptosis in the p53−/− cells as compared to p53+/+ cells, which was correlated with activation of SAPK/JNK, p38 MAPK, and AKT pathways. A transcriptional regulatory network analysis revealed that arsenic activated transcription regulatory elements E2F, Egr1, Trp53, Stat6, Bcl6, Creb2 and ATF4 in the p53+/+ cells, while in the p53−/− cells, arsenic treatment altered transcription factors NFκB, Pparg, Creb2, ATF4, and Egr1. We observed dynamic changes in phosphorylated NFκB p65 (p-NFκB p65) and phosphorylated IKKαβ (p-IKKαβ) in both genotypes from 4 h to 24 h after treatment, significant decreases of p-NFκB p65 and p-IKKαβ in the p53−/− cells, whereas increases of p-NFκB p65 and p-IKKαβ were observed in the p53+/+ cells. Our study confirmed the differential modulation of NFκB pathway by arsenic in the p53+/+ or p53−/− cells and this observation of the differential mechanism of cell death between the p53+/+ and p53−/− cells might be linked to the unique ability of arsenic to act as both a carcinogen and a chemotherapeutic agent.

  • Oxyresveratrol stimulates mucin production in an NAD+-dependent manner in human intestinal goblet cells
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-20
    Dahyun Hwang, HyunA. Jo, Seong-Ho Ma, Young-Hee Lim

    The intestinal mucus layer plays an important role in the management of inflammatory bowel disease. The aim of this study was to investigate the effects of oxyresveratrol (OXY), an antioxidant, on the stimulation of mucin production in human LS 174T goblet cells and the underlying mechanism thereof. OXY increased MUC2 expression at both the mRNA and protein levels. By performing two-dimensional gel electrophoresis, we found that the expression of nicotinic acid phosphoribosyltransferase1 (NaPRT1) in OXY-treated LS 174T cells was greatly increased compared with that in negative control cells. In addition, the NAD+/NADH ratio was increased in proportion to OXY in LS 174T cells. The expression of NAD+-synthesis enzymes, NaPRT1, nicotinamide riboside kinase1 (NRK1) and nicotinamide mononucleotide adenylyltransferase1 (Nmnat1) was significantly increased at both the mRNA and protein levels in OXY-treated LS 174T cells. The inhibition of NaPRT1 and NRK1 did not decrease MUC2 expression after inhibiting by small interfering RNA (siRNA)-NaPRT1 and siRNA-NRK1, respectively; however, inhibition of Nmnat by an Nmnat inhibitor decreased MUC2 expression in a dose-dependent manner. In conclusion, OXY increases NAD+ levels, resulting in the stimulation of MUC2 expression in LS 174T cells. These findings present a novel role for NAD+ in stimulation of MUC2 expression.

  • 更新日期:2018-06-22
  • Diclofenac induced gastrointestinal and renal toxicity is alleviated by thymoquinone treatment
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-20
    İlker Öngüç Aycan, Özlem Elpek, Bahar Akkaya, Ebru Kıraç, Hazal Tuzcu, Sabriye Kaya, Nesil Coşkunfırat, Mutay Aslan

    The aim of this study was to investigate whether thymoquinone (TQ) could alleviate diclofenac (DCLF)-induced gastrointestinal and renal toxicity in rats. Diclofenac was administered via intramuscular injection twice daily for 5 days and TQ was given by gavage for the same period. Hematological and biochemical profiles were measured with autoanalyzers while reactive oxygen/nitrogen species (ROS/RNS) generation and total antioxidant capacity (TAC) were assayed by standard kits. Tissue injuries were evaluated by microscopy and histopathological scoring. Diclofenac treatment caused kidney and liver function test abnormalities, reduced hematocrit and hemoglobin levels but increased WBC and platelet counts. Histopathological findings showed renal tubular damage, gastrointestinal lesions and increased fibrosis in DCLF treated rats. Thymoquinone administration, along with DCLF treatment, attenuated hematological test abnormalities and DCLF induced renal functional impairment as evident by significantly restored serum creatinine and blood urea nitrogen levels. Similarly, TQ treatment significantly alleviated liver function test abnormalities and decreased tissue injury in the stomach and duodenum. Diclofenac treatment caused increased ROS/RNS formation and decreased TAC in the kidney, stomach and duodenal tissue. Thymoquinone administration increased gastrointestinal and renal TAC in DCLF treated rats. These results indicate that TQ could ameliorate gastrointestinal and renal toxicity induced by high dose DCLF treatment.

  • Inhibition of cholinergic and non-cholinergic targets following subacute exposure to chlorpyrifos in normal and high fat fed male C57BL/6J mice
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-21
    George E. Howell III, Sandeep Kondakala, Julie Holdridge, Jung Hwa Lee, Matthew K. Ross

    The effects of obesity on organophosphate pesticide-mediated toxicities, including both cholinergic and non-cholinergic targets, have not been fully elucidated. Therefore, the present study was designed to determine if high fat diet intake alters the effects of repeated exposure to chlorpyrifos (CPS) on the activities of both cholinergic and noncholinergic serine hydrolase targets. Male C57BL/6J mice were placed on either standard rodent chow or high fat diet for four weeks with CPS exposure (2.0 mg/kg) for the last 10 days of diet intake. Exposure to CPS did not alter acetylcholinesterase in the central nervous system, but it did significantly inhibit circulating cholinesterase activities in both diet groups. CPS significantly inhibited hepatic carboxylesterase and fatty acid amide hydrolase and this inhibition was significantly greater in high fat fed animals. Additionally, CPS exposure and high fat diet intake downregulated genes involved in hepatic de novo lipogenesis as well as cytochrome P450 enzymes involved in hepatic xenobiotic metabolism. In summary, the present study demonstrates that high fat diet intake potentiates CPS mediated inhibition of both carboxylesterase and fatty acid amide hydrolase in the liver of obese animals following subacute exposure and suggests obesity may be a risk factor for increased non-cholinergic hepatic CPS toxicity.

  • Prevalence and concentration of ochratoxin A, zearalenone, deoxynivalenol and total aflatoxin in cereal-based products: A systematic review and meta-analysis
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-21
    Amin Mousavi Khaneghah, Yadolah Fakhri, Susan Raeisi, Bahram Armoon, Anderson S. Sant'Ana
  • Teratogenic effects of the neonicotinoid thiacloprid on chick embryos (Gallus gallus domesticus)
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-19
    Antonio Salvaggio, Francesco Antoci, Antonino Messina, Margherita Ferrante, Chiara Copat, Claudia Ruberto, Elena Maria Scalisi, Roberta Pecoraro, Maria Violetta Brundo
  • A systematic review and meta-analysis of metal concentrations in canned tuna fish in Iran and human health risk assessment
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-18
    Jamal Rahmani, Yadolah Fakhri, Ali Miri, Abbas Shahsavani, Zohreh Bahmani, Mauricio A. Urbina, Salvatore Chirumbolo, Hassan Keramati, Bigard Moradi, Abotaleb Bay, Geir Bjørklund
  • The prevalence of aflatoxin M1 in milk of Middle East region: A systematic review, meta-analysis and probabilistic health risk assessment
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-15
    Jamal Rahmani, Solmaz Alipour, Ali Miri, Yadolah Fakhri, Seyed-Mohammad Riahi, Hassan Keramati, Masoud Moradi, Nazak Amanidaz, Rokhsane Hosseini Pouya, Zohreh Bahmani, Amin Mousavi Khaneghah
  • Cytotoxic effects induced by patulin, deoxynivalenol and toxin T2 individually and in combination in hepatic cells (HepG2)
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-15
    Celia Fernández-Blanco, Luigi Elmo, Thomas Waldner, Maria-Jose Ruiz

    Patulin (PAT), deoxynivalenol (DON) and toxin T-2 (T-2) are mycotoxins distributed worldwide in food and feed. Cytotoxicity of the three mycotoxins individually or in combination in human hepatocellular carcinoma (HepG2) cells was evaluated by MTT assay over 24, 48 and 72 h of exposure. The concentration ranges used were 0.625–15 μM for DON, 1.25–50 nM for T-2 and 0.45–7.5 μM for PAT. The IC50 values obtained ranged from 9.30 to 2.53 μM, from 33.69 to 44.37 nM and from 2.66 to 1.17 μM for DON, T-2 and PAT, respectively. The most cytotoxic mycotoxin to HepG2 cells was T-2 followed by PAT and DON. The combination ratios used for the mixtures were 1:3 (DON: T-2), 1:5 (DON: PAT), 1:1.7 (T-2: PAT) and 1:3:5 (DON: T-2: PAT). The mixture with the highest cytotoxic effect was T-2+PAT, followed by DON + T-2+PAT, DON + T-2 and DON + PAT respect to the cytotoxic effect of their individuals. In the combinations, at low fa an antagonistic effect was detected, and this effect changes the shape of the combination to additive effect at high fa in the mixtures.

  • Discrimination of three Siegesbeckiae Herba species using UPLC-QTOF/MS-based metabolomics approach
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-01-03
    Hong-Xun Tao, Wei Xiong, Guan-Ding Zhao, Yu Peng, Zhang-Feng Zhong, Liang Xu, Ran Duan, Karl W.K. Tsim, Hua Yu, Yi-Tao Wang

    The plant origin is one of the most important factors for the quality control of traditional Chinese medicines (TCMs) and highly affected on their safety and effectiveness in clinical applications. Multi-origin has been widely observed for many TCMs. Siegesbeckiae Herba (SH) is a traditional anti-rheumatic TCM which is originated from the plants of Siegesbeckia pubescens Makino (SP), S. orientalis L. (SO), and S. glabrescens Makino (SG). In the present study, an UPLC-QTOF/MS method were validated and successfully applied for the determination of the chemical profiles in the three SH species. The data were statistical analyzed with the OPLS-DA analysis and One-Way ANOVA F-test. Obvious differences in chemistry were observed in different SH species and 40 components were identified. Finally, 6 components were selected as potential chemical markers for the discrimination of SP, SO and SG based on the characteristic distribution in individual SH species.

  • The effect of Zataria multiflora Boiss Essential oil on the growth and citrinin production of Penicillium citrinum in culture media and cheese
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-14
    Fateme Akrami Mohajeri, Ali Misaghi, Hamidreza Gheisari, Afshin Akhondzadeh Basti, Assieh Amiri, Sayyed Razi Ghalebi, Zahra Derakhshan, Roohollah Dehghani Tafti

    The effect of Zataria multiflora Boiss Essential oil (EO) on the growth, spore production, and citrinin production of Penicellium citrinum PTCC 5304 in the culture media as well as Iranian ultra-filtered white cheese in brine was investigated. Radial growth and spore production on the potato dextrose agar (PDA) were effectively inhibited by EO in a dose-dependent manner. At 200 ppm, the radial growth and sporulation declined by 92% and 100%, respectively. The growth was completely prevented at 400 ppm of EO on PDA and the minimum fungicidal concentration (MFC) of the oil was estimated at 400 ppm. Furthermore, the oil also significantly suppressed the mycelial growth and citrinin production in broth medium at all investigated concentrations (P < 0.05). At 150 ppm of EO, the citrinin accumulation and mycelial growth reduced by 88.6% and 89.6%, respectively. The EO was tested at all concentrations and the findings show an inhibitory effect of P. citrinum against the radial fungal growth and citrinin production in cheese. However, no concentration of EO could completely inhibit the growth and production of citrinin in cheese. We therefore concluded that Zataria multiflora has the potential to substitute the antifungal chemicals as a natural inhibitor to control the growth of molds in foods such as cheese.

  • Chitosan extracted from marine biowaste mitigates staphyloxanthin production and biofilms of Methicillin- resistant Staphylococcus aureus
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-13
    Durairajan Rubini, Sanaulla Farisa Banu, B. Narayanan Vedahari, Durai Ramyadevi, Shanmugaraj Gowrishankar, Shunmugiah Karutha Pandian, Paramasivam Nithyanand
  • Acteoside protects against 6-OHDA-induced dopaminergic neuron damage via Nrf2-ARE signaling pathway
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-12
    Maiquan Li, Fei Zhou, Tao Xu, Huaxin Song, Baiyi Lu
  • Glyphosate induces growth of estrogen receptor alpha positive cholangiocarcinoma cells via non-genomic estrogen receptor/ERK1/2 signaling pathway
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-08
    Narongrit Sritana, Tawit Suriyo, Jantamas Kanitwithayanun, Benjaporn Homkajorn Somgvasin, Apinya Thiantanawat, Jutamaad Satayavivad

    Previous studies showed that glyphosate stimulates breast cancer cell growth via estrogen receptors. The present study investigated the effect of glyphosate on the estrogen signaling pathway involved in the induction of cholangiocarcinoma (CCA) cell growth. HuCCA-1, RMCCA-1 and MMNK-1 were chosen for comparison. The effects of glyphosate on cell growth, cell cycle and molecular signaling pathways were measured. The results showed that HuCCA-1 cells expressed estrogen receptor alpha (ERα), while ERα was not detected in RMCCA-1 and MMNK-1 cells. ERα was mostly expressed in cytoplasmic compartment of HuCCA-1 cells. Estradiol (E2) (10−11-10−5 M) induced cell proliferation in HuCCA-1 but not in RMCCA-1 and MMNK-1 cells. Glyphosate at the same concentration range also induced HuCCA-1 cell proliferation. The S phase of the cell cycle, and protein levels of the cyclin family were significantly increased after treatment of glyphosate or E2. Both compounds also induced the expression of proliferative signaling–related proteins including ERα, VEGFR2, pERK, PI3K(p85), and PCNA. These effects of glyphosate and E2 were abolished by the ER antagonist, 4-hydroxytamoxifen and U0126, a MEK inhibitor. The data from this study indicate that glyphosate can induce cell growth in ERα positive CCA cells through non-genomic estrogen receptor/ERK1/2 signaling pathway.

  • Implication of dietary phthalates in breast cancer. A systematic review
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-08
    Pietro Zuccarello, Gea Oliveri Conti, Federico Cavallaro, Chiara Copat, Antonio Cristaldi, Maria Fiore, Margherita Ferrante

    Phthalates are endocrine-disrupting for their ability to change the normal function of human endocrine system. Their action on the reproductive system, both on male and female, is the most one investigated by international scientific community. The aim of this systematic review was to gather the available information regarding the role of phthalates on breast carcinogenesis focusing our research in their intake through the diet. Research was performed according the PRISMA methodology and 25 scientific articles published between 2000 and 2018 were selected. The main source of exposure to phthalates is diet, mainly through the consumption of food and beverages wrapped in different plastic packaging. Several in vitro studies suggest that certain phthalates may be associated to breast cancer since they can bind and activate the estrogen receptors. However, results of epidemiological studies are debated, yet. It's necessary to plan the future studies more carefully to have more representative data on phthalate exposure by replacing urinary matrix with piliferous one, by including as confounding factors not only the other risk factors but also prevention one as diet and miRNA expression and, finally, by direct the study considering not only the estrogenic activity of phthalates and so including also the ER negative tumors.

  • In vivo antitumor activity of by-products of Passiflora edulis f. flavicarpa Deg. Rich in medium and long chain fatty acids evaluated through oxidative stress markers, cell cycle arrest and apoptosis induction
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-07
    Nádia S.R.S. Mota, Maicon R. Kviecinski, Rodrigo C. Zeferino, Daniela A. de Oliveira, Lizandra C. Bretanha, Sandra R.S. Ferreira, Gustavo A. Micke, Danilo Wilhelm Filho, Rozangela C. Pedrosa, Fabiana Ourique

    Antiinflammatory and antitumor activity has been reported in Passiflora edulis (yellow passion fruit) nevertheless the intrinsic mechanisms of action are not fully elucidated. The present study aimeds to perform a comparison between the antitumor activity involving the crude extract (HCE) and the supercritical fluid extract with ethanol as co-solvent (SFEtOH) from P. edulis f. flavicarpa Deg. The in vitro cytotoxicity was evaluated in MCF-7 cells, while the in vivo antitumor activity was assessed in male Balb/c mice inoculated with Ehrlich carcinoma cells. SFEtOH exhibited higher antitumor activity compared to HCE. Wherein, SFEtOH showed an EC50 of 264.6 μg/mL against MCF-7 cells as well as an increased inhibition of tumor growth of 48.5% (p < 0.001) in male Balb/c mice, thereby promoting an increased mice lifespan to approximately 42%. Moreover, SFEtOH caused lipid (p < 0.001) and protein (p < 0.001) oxidation by increasing glutathione redox cycle activity while decreased the thioredoxin reductase activity (p < 0.001). SFEtOH also induced oxidative DNA damage in Ehrlich ascites carcinoma (EAC) cells leading to G2/M cycle arrest and has increased apoptotic cells up to 48.2%. These data suggest that the probable mechanisms of antitumor effect are associated to the lipid, protein and DNA damage, leading to cell cycle arrest and triggering apoptosis via mitochondrial pathway, should be probable due to the presence of medium and long chain fatty acids such as lauric acid.

  • Safety assessment of the Cistanche tubulosa health food product Memoregain®: Genotoxicity and 28-day repeated dose toxicity test
    Food Chem. Toxicol. (IF 3.977) Pub Date : 2018-06-07
    Po-Lin Liao, Ching-Hao Li, Ling-Shan Tse, Jaw-Jou Kang, Yu-Wen Cheng

    The pharmacological effects of Cistanches Herba, known as "Ginseng of the desert", have been extensively studied. In this study, we aimed to assess the genotoxic and oral toxic effects of the Cistanche tubulosa health food product Memoregain® using in vitro and in vivo tests. Ames tests using five strains of Salmonella typhimurium showed no signs of increased reverse mutation upon exposure to Memoregain® up to a concentration of 5 mg/plate. Exposure of Chinese hamster ovary (CHO-K1) cells to Memoregain® did not increase the frequency of chromosomal aberrations in vitro. Moreover, Memoregain® treatment did not affect the proportions of immature to total erythrocytes or the number of micronuclei in the immature erythrocytes of ICR mice. Additionally, after 28-day repeated oral dose toxicity tests (0, 0.15, 0.3, and 0.5g/kg body weight) in rats, no observable adverse effects were found. These toxicological assessments supported the safety of Memoregain® for human consumption.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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