Carcinogenic effect of low doses of polycyclic and heterocyclic aromatic hydrocarbons and amines and lack of protection by inulin supplementation.

Evidence suggests that meat processing and heat treatment may increase cancer risk through exposure to potentially carcinogenic compounds, polycyclic aromatic hydrocarbons (PAHs), and heterocyclic aromatic amines (HAAs). This study aims to investigate the effect of low concentrations of PAHs and HAAs (from 1 to 100 µmol/L/24h and 48h) in colorectal tumor cells (HT-29, HCT116, and LS174T) and to evaluate the effect of PAHs in the presence of inulin in mice. In vitro, the 4-PAHs have no effect on healthy colon cells but decreased the viability of the colorectal tumor cells and activated the mRNA and protein expressions of CYP1A1 and CYP1B1. In vivo, in mice with colitis induced by 3% DSS, the 4-PAHs (equimolar mix at 50,100, 150 mg/kg.bw, orally 3 times a week for 3 weeks) induced a loss of body weight and tumor formation. Inulin (10 g/L) had no effect on colon length and tumor formation. A significant decrease in the loss of b.w was observed in inulin group as compared to the fiber free group. These results underscore the importance of considering the biological association between low-dose exposure to 4-HAPs and diet-related colon tumors.

N-Heterocyclic Carbene Iron Complexes as Anticancer Agents: In Vitro and In Vivo Biological Studies.

Cisplatin and its derivatives are commonly used in chemotherapeutic treatments of cancer, even though they suffer from many toxic side effects. The problems that emerge from the use of these metal compounds led to the search for new complexes capable to overcome the toxic side effects. Here, we report the evaluation of the antiproliferative activity of Fe(II) cyclopentadienyl complexes bearing n-heterocyclic carbene ligands in tumour cells and their in vivo toxicological profile. The in vitro antiproliferative assays demonstrated that complex Fe1 displays the highest cytotoxic activity both in human colorectal carcinoma cells (HCT116) and ovarian carcinoma cells (A2780) with IC50 values in the low micromolar range. The antiproliferative effect of Fe1 was even higher than cisplatin. Interestingly, Fe1 showed low in vivo toxicity, and in vivo analyses of Fe1 and Fe2 compounds using colorectal HCT116 zebrafish xenograft showed that both reduce the proliferation of human HCT116 colorectal cancer cells in vivo.

Application of the Target Lipid Model to Assess Toxicity of Heterocyclic Aromatic Compounds to Aquatic Organisms.

Heterocyclic aromatic compounds can be found in crude oil and coal and often co-exist in environmental samples with their homocyclic aromatic counterparts. The target lipid model (TLM) is a modeling framework that relates aquatic toxicity to the octanol-water partition coefficient (KOW ) that has been calibrated and validated for hydrocarbons. A systematic analysis of the applicability of the TLM to heterocyclic aromatic compounds has not been performed. The objective of the present study was to compile reliable toxicity data for heterocycles and determine whether observed toxicity could be successfully described by the TLM. Results indicated that the TLM could be applied to this compound class by adopting an empirically derived coefficient that accounts for partitioning between water and lipid. This coefficient was larger than previously reported for aromatic hydrocarbons, indicating that these heterocyclic compounds exhibit higher affinity to target lipid and toxicity. A mechanistic evaluation confirmed that the hydrogen bonding accepting moieties of the heteroatoms helped explain differences in partitioning behavior. Given the TLM chemical class coefficient reported in the present study, heterocyclic aromatics can now be explicitly incorporated in TLM-based risk assessments of petroleum substances, other products, or environmental media containing these compounds. Environ Toxicol Chem 2021;40:3000-3009. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Recent advancements in anti-leishmanial research: Synthetic strategies and structural activity relationships.

Leishmaniasis is a parasitic neglected tropical disease caused by various species of Leishmania parasite. Despite tremendous advancements in the therapeutic sector and drug development strategies, still the existing anti-leishmanial agents are associated with some clinical issues like drug resistance, toxicity and selectivity. Therefore, several research groups are continuously working towards the development of new therapeutic candidates to overcome these issues. Many potential heterocyclic moieties have been explored for this purpose including triazoles, chalcones, chromone, thiazoles, thiosemicarbazones, indole, quinolines, etc. It is evident from the literature that the majority of anti-leishmanial agents act by interacting with key regulators including PTR-I, DHFR, LdMetAP1, MAPK, 14 α-demethylase and pteridine reductase-I, etc. Also, these tend to induce the production of ROS which causes damage to parasites. In the present compilation, authors have summarized various significant synthetic procedures for anti-leishmanial agents reported in recent years. A brief description of the pharmacological potentials of synthesized compounds along with important aspects related to structural activity relationship has been provided. Important docking outcomes highlighting the possible mode of interaction for the reported compounds have also been included. This review would be helpful to the scientific community to design newer strategies and also to develop novel therapeutic candidates against leishmaniasis.

Shrimp as a substantial source of carcinogenic heterocyclic amines.

In the present work, fifteen mutagenic/carcinogenic heterocyclicamines (HAs)were studied in cooked Caridean shrimp (pink) and Penaeid shrimp (tiger, white and brown). The cooking methods were used as stir-frying, broiling and steaming under controlled temperature and time, and HAs determination was performed by SPE/UPLC-ESI-MS/MS. HAs 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-Amino-1,6-dimethyl-imidazo[4,5-b]pyridine (DMIP), 1-Methyl-9H-pyrido[3,4-b]indole (Harman) and 9H-pyrido[3,4-b]indole (Norharman) were identified (0.05-22.48 ng/g) in all stir-fried and broiled shrimp, whereas 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) was only found (0.08-0.35 ng/g) in stir-fried shrimp. HAs 2-Amino-3,7,8-trimethyl-imidazo[4,5-f]quinoxaline (7,8-DiMeIQx) and, α-carbolines 2-Amino-9H-pyrido[2,3-b]indole (AαC) and 2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC), γ-carbolines 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-Amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and δ-carbolines 2-Amino-6-methyldipyrido[1,2-α:3́,2́-d]imidazole (Glu-P-1) and 2-Aminodipyrido[1,2-α:3́,2́-d]imidazole (Glu-P-2) were not detected or found below quantification limit. Brown shrimp (stir-fried) appeared to be more contaminated which constitutes total HAs (81.93 ng/g) followed by pink (70.41 ng/g), tiger (53.02 ng/g) and white (33.57 ng/g). Steaming method does not yield any HAs, and the cause might be elucidate that shrimp were not directly in contact with cooking pan or fire which affect the HAs formation. Food precursors (protein, moisture, fat, creatine and glucose) were also measured in raw and cooked shrimp to investigate the influence on HAs formation. Creatine (3.85 mg/g) and glucose (0.43 mg/g) were found at higher concentrations in brown shrimp, generates high amounts of HAs. Our findings have illustrated that the cooking method, shrimp types and precursors are the main contributors to the formation of HAs. The outcomes from this work could be applied to estimate the HAs human intake globally and add to steaming cooking method in such types of food products that diminish the risk of HAs exposure, and thus to get healthier food quality and security.

BODIPY based red emitters: Synthesis, computational and biological studies.

Donor-Acceptor type BODIPYs with strong absorption and fluorescence in the red region (550-800 nm) are reported. The aromatic groups like N-butylcarbazole/ N-butylphenothiazine/ benzothiadiazole were attached to the C-8 position of the BODIPY core with furan or thiophene spacers. TD-DFT studies indicated significant charge distribution between C-8 aromatic heterocycles and BODIPY core in all the molecules. The in-vitro studies of the N-butylcarbazole substituted BODIPYs indicated significant localization in the endoplasmic reticulum and lysosomes of the cancer cells. The BODIPYs showed decent cytotoxicity after 48 h incubation period (14.9 to 31.8 µM) in HeLa and A549 cancer cells, indicating their potential application as theranostic agents.

The molecular effect of 1,4,7-triazacyclononane on oxidative stress parameters in human hepatocellular carcinoma (HepG2) cells.

Antibiotic resistance poses a great threat to human, animal and environmental health. ß-Lactam antibiotics have been successful in combating bacterial infections. However, the overuse, inappropriate prescribing, unavailability of new antibiotics and regulation barriers have exacerbated bacterial resistance to these antibiotics. 1,4,7-Triazacyclononane (TACN) is a cyclic organic tridentate inhibitor with strong metal-chelating abilities that has been shown to inhibit ß-lactamase enzymes and may represent an important breakthrough in the treatment of drug-resistant bacterial strains. However, its cytotoxicity in the liver is unknown. This study aimed to determine the effect of TACN on oxidative stress in HepG2 cells. The HepG2 cells were treated with 0 to 500 µM TACN for 24 hours to obtain an IC50 for use in subsequent assays. Free radicals were measured using the thiobarbituric acid reactive substance and nitric oxide synthase assays, respectively, while antioxidant levels were assessed using luminometry (glutathione [GSH] and adenosine triphosphate [ATP]) and Western blot analysis (SOD, catalase, GPx-1, HSP70 and Nrf2). Percentage survival fluctuated as TACN concentration increased with a calculated IC50 of 545 µM. A slight increase in HSP70 and Nrf2 expression indicated the presence of stress and a response against it, respectively. However, free radical production was not increased as indicated by decreased malondialdehyde levels and reactive nitrogen species. Glutathione levels increased slightly, while ATP levels were marginally altered. The results suggest that TACN does not induce oxidative stress in HepG2 cells and can be exploited as a potential inhibitor.

Phytochemical-Rich Antioxidant Extracts of Vaccinium Vitis-idaea L. Leaves Inhibit the Formation of Toxic Maillard Reaction Products in Food Models.

Thermal treatment of proteinaceous foods generates heat-induced Maillard reaction substances including toxic advanced glycation end products (AGEs) and heterocyclic amines (HAs). It is known that plant phenolic compounds may influence Maillard reaction. This study investigated the impact of lingonberry leaf extracts on the formation of Nε -(carboxymethyl)lysine (CML) and Nε -(2-furoylmethyl)-L-lysine (furosine) in milk model system and HAs in meat-protein and meat model systems. In addition, lingonberry leaf extracts obtained by different solvents were characterized by radical scavenging, Folin-Ciocalteu assays and ultrahigh pressure liquid chromatography quadruple-time-of flight mass spectrometry (UPLC-qTOF-MS). Water extract (WE) stronger suppressed CML than furosine formation in milk model system: CML levels were reduced by nearly 40%. Moreover, quinic acid and catechin, which were abundant in WE, were effective in inhibiting CML and furosine formation. WE and acetone extract (AE) at 10 mg/mL significantly inhibited HAs formation in both model systems. However, higher suppressing effect on HAs formation showed AE, which had lower antioxidant capacity and total phenolic content values than WE. WE contained higher amounts of hydroxycinnamic acids, proanthocyanidins and flavonols, while AE was richer in flavan-3-ols and arbutin derivatives. It indicates that the composition of phenolics might be a major factor for explaining different effect of extracts from the same plant on HAs formation. In general, the results suggest that lingonberry leaves is a promising source of phytochemicals for inhibiting toxic Maillard reaction products and enriching foods with plant bioactive compounds. PRACTICAL APPLICATION: The increased consumption in processed foods has been linked with the increased risks of various diseases, while thermal food processing is required to develop flavor, insure safety, and extend shelf life. Therefore, developing effective technological means for inhibiting the formation of heat-induced toxic substances is an important task. This study showed a potential of lingonberry leaf extracts containing health beneficial phytochemicals to suppress the formation of toxic Maillard reaction products during heating of milk and meat.

Interactions of preservatives in meat processing: Formation of carcinogenic compounds, analytical methods, and inhibitory agents.

Meat products are important for balanced diets because of their nutritional richness. However, noxious compounds may be formed by interactions among reactants and specific conditions in processed meats. N-nitroso compounds, heterocyclic aromatic amines, polycyclic aromatic hydrocarbons, 1,4-dinitro-2-methyl pyrrole (DNMP), and ethyl nitrolic acid (ENA) are among the main compounds of toxicological concern. This review corroborates the International Agency for Research on Cancer (IARC)'s decision to classify those foodstuffs as carcinogenic to humans. Furthermore, this paper also aimed at clarifying how noxious compounds are formed in meat products, as well as their health effects for consumers. The preservatives abuse and the use of forbidden additives may increase the formation of carcinogens. Risks are not only due to preservatives, since some compounds are formed during processing or digestion, without clear link to any additive. Regulation should set specific residue limits for other noxious compounds in meat products, such as DNMP and ENA. The scope of control programs should be extended instead of assessing the proper use of additives only. Thus, reliable analytical methods for the quantitation of carcinogens should be available. Fermentative and enzymatic processes for bioconversion are among the main strategies to solve these problems in foodstuffs. The use of antioxidants is the most common approach, because of its low cost and effectiveness. In the future, the IARC classification should rather consider different categories of processing, as well as the chemical and microbiological composition of meat products. Further studies are still required to clarify the increase on cancer risk due to the consumption of meat products and to elucidate the main mechanisms of carcinogenicity. Notwithstanding, such carcinogens cannot be neglected, but continuously investigated, including their health implications in relation to other foods.

Impact of gadolinium-based contrast agents on the growth of fish cells lines.

The present study was the first approach conducted under environmental concentrations of Gd-DOTA and Gd-DTPA-BMA to assess cellular impacts of these compounds. Gd-DOTA (Gadoteric acid) is one of the most stable contrast agent, currently used as Dotarem® formulation during Magnetic Resonance Imaging exams. The study was mainly performed on a Zebra Fish cell line (ZF4; ATCC CRL-2050). At the concentrations of 0.127 nM and 63.59 nM (respectively 20 ng and 10 µg of Gd/L), we did not observed any toxicity of Dotarem® but a slowdown of the cell growth was clearly measured. The effect is independent of medium renewing during 6 days of cell culturing. The same effect was observed i-with Gd-DOTA on another fish cell line (RT W1 gills; ATCC CRL-2523) and ii-with another contrast agent (Gd-DTPA-BMA - Omniscan®) on ZF4 cells. On the ZF4 cell line, the diminution of the cell growth was of the same order during 20 days of exposure to a culture medium spiked with 63.59 nM of Dotarem® and was reversible within the following 8 days when Dotarem® was removed from the medium. As shown by using modified DOTA structure (Zn-DOTA), the effect may be due to the chelating structure of the contrast agent rather than to the Gd ion. Until now, the main attention concerning the impact of Gd-CA on living cells concerned the hazard due to Gd release. According to our results, quantifying the presence of Gd-CA chelating structures in aquatic environments must be also monitored.

Synthetic heterocyclic candidates as promising α-glucosidase inhibitors: An overview.

α-Glucosidase enzyme inhibition is an effective therapeutic decorum in the treatment of type 2 diabetes mellitus. Since 1990, three α-glucosidase inhibitors are known to exist clinically, Acarbose, Voglibose and Miglitol. Side effects and long synthetic routes to access them forced the researchers to move their focus to discover simple and small heterocyclic motifs that work as promising α-glucosidase inhibitors and may eventually lead to the management of postprandial hyperglycemic condition in T2DM. In this regards, this review deals with recently discovered heterocyclic molecules that have been evaluated to exhibit inhibition of α-glucosidase enzyme.

Ecotoxicity of Nitrogen, Sulfur, or Oxygen Heterocycles and Short-Chained Alkyl Phenols Commonly Detected in Contaminated Groundwater.

Nitrogen, sulfur, or oxygen heterocyclic aromatic hydrocarbons (NSO-HETs) and short-chained alkyl phenols (SCAPs) are commonly detected in groundwater at contaminated sites and in the surrounding environment. It is now scientific consensus that these chemicals pose a risk to human and ecosystem health. However, toxicity data are comparably fragmentary, and only few studies have addressed the ecotoxicity of NSO-HETs and SCAPs in a systematic and comparative fashion. To overcome this shortcoming, we tested 18 SCAPs, 16 NSO-HETs, as well as the homocyclic hydrocarbons indane and indene in the Microtox® assay with Aliivibrio fischeri, the growth inhibition test with Desmodesmus subspicatus, the acute immobilization assay with Daphnia magna, as well as the fish embryo toxicity test with embryos of the zebrafish (Danio rerio). Because of the physicochemical properties of the tested chemicals (limited water solubility, volatility, and sorption to test vessels), actual exposure concentrations in test media and their dissipation over time were analytically quantified by means of gas chromatography with mass spectrometry. Analytically corrected effect levels (median effect and lethal concentrations) ranged from 0.017 to 180 mg L-1 , underlining the environmental relevance of some NSO-HETs and SCAPs. Para-substituted phenols showed the overall greatest toxicities in all 4 toxicity tests. We provide, for the first time, a complete high-quality data set in support of better environmental risk assessments of these chemicals. Environ Toxicol Chem 2019;38:1343-1355. © 2019 SETAC.

Dietary Heterocyclic Amine Intake and Colorectal Adenoma Risk: A Systematic Review and Meta-analysis.

BACKGROUND: Heterocyclic amines (HCA) are potent carcinogenic substances formed in meat. Because of their mutagenic activity, they may increase the risk of colorectal adenomas, which are the precursors of colorectal cancer, one of the most prevalent cancers worldwide. The aim of this meta-analysis was to synthesize the knowledge about the intake of HCAs and its associations with CRA. METHODS: We conducted a systematic search in PubMed and EMBASE. We used odds ratios (OR); or relative risks, RR) from every reported intake and compared the highest versus lowest level of dietary HCAs. In addition, we assessed a dose-response relationship. RESULTS: Twelve studies on HCA intake and risk of CRA were included in our analysis. We observed a statistically significant association when comparing top versus bottom intake category of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [PhIP; OR = 1.20; 95% confidence interval (CI) = 1.12-1.29], 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx; OR = 1.20; 95% CI = 1.08-1.34), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx; OR = 1.16; 95% CI = 1.05-1.27), benzo(a)pyrene (BaP; OR = 1.15; 95% CI = 1.04-1.27), and mutagenicity index (OR = 1.22; 95% CI = 1.06-1.41). Furthermore, we observed a significant dose-response effect for PhIP, MeIQx, and mutagenicity index. CONCLUSIONS: This meta-analysis suggests that there is a positive association of HCAs, BaP, mutagenicity index with risk of CRA. In addition, our dose-response analyses showed an increased risk of CRA for PhIP, MeIQx, and mutagenicity index. IMPACT: This study provides evidence for a positive association between the dietary intake of meat mutagens and CRA risk.

Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues?: A Comparative Gadoterate Versus Gadodiamide Study in Juvenile and Adult Rats.

OBJECTIVES: The main objective of the study was to assess the effect of age on target tissue total gadolinium (Gd) retention after repeated administration of gadodiamide (linear) or gadoterate (macrocyclic) Gd-based contrast agent (GBCA) in rats. The secondary objective was to assess the potential developmental and long-term consequences of GBCA administration during neonatal and juvenile periods. MATERIALS AND METHODS: A total of 20 equivalent human clinical doses (cumulated dose, 12 mmol Gd/kg) of either gadoterate or gadodiamide were administered concurrently by the intravenous route to healthy adult and juvenile rats. Saline was administered to juvenile rats forming the control group. In juvenile rats, the doses were administered from postnatal day 12, that is, once the blood-brain barrier is functional as in humans after birth. The tests were conducted on 5 juvenile rats per sex and per group and on 3 adult animals per sex and per group. T1-weighted magnetic resonance imaging of the cerebellum was performed at 4.7 T during both the treatment and treatment-free periods. Behavioral tests were performed in juvenile rats. Rats were euthanatized at 11 to 12 weeks (ie, approximately 3 months) after the last administration. Total Gd concentrations were measured in plasma, skin, bone, and brain by inductively coupled plasma mass spectrometry. Cerebellum samples from the juvenile rats were characterized by histopathological examination (including immunohistochemistry for glial fibrillary acidic protein or GFAP, and CD68). Lipofuscin pigments were also studied by fluorescence microscopy. All tests were performed blindly on randomized animals. RESULTS: Transient skin lesions were observed in juvenile rats (5/5 females and 2/4 males) and not in adult rats having received gadodiamide. Persisting (up to completion of the study) T1 hyperintensity in the deep cerebellar nuclei (DCNs) was observed only in gadodiamide-treated rats. Quantitatively, a slightly higher progressive increase in the DCN/brain stem ratio was observed in adult rats compared with juvenile rats, whereas no difference was noted visually. In all tissues, total Gd concentrations were higher (10- to 30-fold higher) in the gadodiamide-treated groups than in the gadoterate groups. No age-related differences were observed except in bone marrow where total Gd concentrations in gadodiamide-treated juvenile rats were higher than those measured in adults and similar to those measured in cortical bone tissue. No significant treatment-related effects were observed in histopathological findings or in development, behavior, and biochemistry parameters. However, in the elevated plus maze test, a trend toward an anxiogenic effect was observed in the gadodiamide group compared with other groups (nonsignificant). Moreover, in the balance beam test, a high number of trials were excluded in the gadodiamide group because rats (mainly males) did not completely cross the beam, which may also reflect an anxiogenic effect. CONCLUSIONS: No T1 hyperintensity was observed in the DCN after administration of the macrocyclic GBCA gadoterate regardless of age as opposed to administration of the linear GBCA gadodiamide. Repeated administration of gadodiamide in neonatal and juvenile rats resulted in similar total Gd retention in the skin, brain, and bone to that in adult rats with sex having no effect, whereas Gd distribution in bone marrow was influenced by age. Further studies are required to assess the form of the retained Gd and to investigate the potential risks associated with Gd retention in bone marrow in juvenile animals treated with gadodiamide. Regardless of age, total Gd concentration in the brain and bone was 10- to 30-fold higher after administration of gadodiamide compared with gadoterate.

Synthesis and Spectral Characterization of Asymmetric Azines Containing a Coumarin Moiety: The Discovery of New Antimicrobial and Antioxidant Agents.

Nine unsymmetrical azines containing a coumarin moiety were prepared by the reaction of the hydrazone of 4-hydroxy-3-acetylcoumarin with differently substituted aromatic aldehydes. The azines were fully spectrally characterized, including a complete assignment of 1 H- and 13 C-NMR resonances, and were assessed for their acute toxicities in the Artemia salina model. Their free radical scavenging activities were tested in the DPPH assay, and in vitro antimicrobial activities were determined against seven bacterial and two fungal strains. The azines containing a p-hydroxyphenyl group were shown to be the most effective antimicrobial agents, and in the case of resistant strains of Staphylococcus aureus and Acinetobacter baumannii, the activity was comparable to that of chloramphenicol. The derivative having a 3,5-dimethoxy-4-hydroxyphenyl group exhibited pronounced antioxidant power reacting rapidly and in 1 : 1 mol ratio with the DPPH radical.

Occurrence of Heterocyclic Amines in Commercial Fast-Food Meat Products Available on the Chinese Market and Assessment of Human Exposure to these Compounds.

Heterocyclic amines (HCAs) have been identified as highly mutagenic and are risk factors for human cancer. In recent years, the intake of fast-food meat products has increased exponentially due to their convenience. Therefore, it is important to assess the health risks of HCAs and provide useful public dietary guidelines. Eight fast-food meat products were selected from the Chinese market, including chicken, beef, and fish, to evaluate their health risk in conjunction with HCAs. Crispy chicken drumsticks contained the maximum level of total HCAs (24.18 ± 3.57 ng/g), followed by crispy fried chicken burgers (19.99 ± 1.41 ng/g) and traditional Chinese nuggets (19.17 ± 1.23 ng/g), whereas shrimp cake burgers had the lowest levels (13.17 ± 1.77 ng/g). Crispy chicken drumsticks (men: 169.12 ng/day, women: 108.70 ng/day), hot chicken wings (men: 126.32 ng/day, women: 142.11 ng/day), and crispy fried chicken burgers (men: 129.78 ng/day, women: 59.91 ng/day) were found to provide the highest dietary intake of HCAs in both genders, which may lead to an increase in colorectal and breast cancers. PRACTICAL APPLICATIONS: The rapid expansion of the Chinese fast-food industry has promoted serious health problems, such as colorectal cancer and some cardiovascular diseases. Several epidemiological studies revealed that a high intake of processed meats may increase the risk of cancer in humans because cooking food proteins, such as meat, at high temperatures could produce high levels of carcinogenic compounds, such as HCAs. Because of the vast variation in eating habits, preparation methods and the frequency of meat consumption, it is important to evaluate the accurate level of HCAs in commercially available fast-food meat products with the aim to clarify the association between processed meats and the health risk.

A Novel Chemiluminescent Probe Based on 1,2-Dioxetane Scaffold for Imaging Cysteine in Living Mice.

A novel chemiluminescent probe for detection of cysteine (Cys) from other biothiols has been reported by utilizing the excellent chemiluminescent Schaap's adamantylidene-dioxetane scaffold. After careful assessment, the probe CL-Cys could detect Cys with high sensitivity and total light photons increased by 28-fold after the probe was treated with Cys, with the detection limit of 7.5 × 10-8 M. Finally, CL-Cys was further utilized for the chemiluminescent imaging of endogenous Cys in a living mouse. In general, this probe has a remarkable ability to detect Cys, which provides a valuable method for interrogation of the Cys roles in more biological and pathological processes.

Synthesis and Biological Evaluation of Rhein-Based MRI Contrast Agents for in Vivo Visualization of Necrosis.

Early and accurate assessment of therapeutic response to anticancer therapy plays an important role in determining treatment planning and patient management in clinic. Magnetic rseonance imaging (MRI) of necrosis that occurs after cancer therapies provides chances for that. Here, we reported three novel MRI contrast agents, GdL1, GdL2, and GdL3, by conjugating rhein with gadolinium 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetic acid (Gd-DOTA) through different linkers. The T1 relaxivities of three probes (7.28, 7.35, and 8.03 mM-1 s-1) were found to be higher than that of Gd-DOTA (4.28 mM-1 s-1). Necrosis avidity of GdL1 was evaluated on the rat models of reperfused liver infarction (RLI) by MRI, which showed an increase of T1-weighted contrast between necrotic and normal liver during 0.5-12 h. Besides, L1 was also labeled with 64Cu to assess its necrosis avidity on rat models of RLI and muscle necrosis (MN) by a γ-counter. The uptakes of 64CuL1 in necrotic liver and muscle were higher than those in normal liver and muscle ( P < 0.05). Then, the ability of GdL1 to assess therapeutic response was tested on rats bearing Walker 256 breast carcinoma injected with a vascular disrupting agent CA4P by MR imaging. The signal intensity of tumoral necrosis was strongly enhanced, and the contrast ratio between necrotic and viable tumor was 1.63 ± 0.11 at 3 h after administration of GdL1. Besides, exposed DNA in necrosis cells may be an important mechanism of three probes targeting to necrosis cells. In summary, GdL1 may serve as a promising MRI contrast agent for accurate assessment of treatment response.

Genotoxicity of heterocyclic amines (HCAs) on freshly isolated human peripheral blood mononuclear cells (PBMC) and prevention by phenolic extracts derived from olive, olive oil and olive leaves.

In this study we investigated the genotoxic potential of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, (PhIP); 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline, (IQ); 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline, (MeIQx) and 2-amino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxaline (DiMeIQx) on human freshly isolated peripheral blood mononuclear cells (PBMC) by the comet assay. The preventive ability of three different phenolic extracts derived from olive (O-PE), virgin olive oil (OO-PE) and olive leaf (OL-PE) on PhIP induced DNA damage was also investigated. PhIP and IQ induced a significant DNA damage at the lowest concentration tested (100 µM), while the genotoxic effect of MeIQx and DiMeIQx become apparent only in the presence of DNA repair inhibitors Cytosine b-D-arabinofuranoside and Hydroxyurea (AraC/HU). The inclusion of metabolic activation (S9-mix) in the culture medium increased the genotoxicity of all HCAs tested. All three phenolic extracts showed an evident DNA damage preventive activity in a very low concentration range (0.1-1.0 µM of phenols) which could be easily reached in human tissues "in vivo" under a regular intake of virgin olive oil. These data further support the observation that consumption of olive and virgin olive oil may prevent the initiation step of carcinogenesis. The leaf waste could be an economic and simple source of phenolic compounds to be used as food additives or supplements.

Four selected high molecular weight heterocyclic aromatic hydrocarbons: Ecotoxicological hazard assessment, environmental relevance and regulatory needs under REACH.

Little is known about the ecotoxicity of heterocyclic aromatic hydrocarbons (NSO-HETs) to aquatic organisms. In the environment, NSO-HETs have been shown to occur in a strong association with their unsubstituted carbocyclic analogues, the polycyclic aromatic hydrocarbons (PAH), for which much more information is available. The present study addressed this issue by investigating the toxicity of four selected NSO-HETs in green algae (Desmodesmus subspicatus), daphnids (Daphnia magna) and fish embryos (Danio rerio). The four high molecular weight NSO-HETs dibenz[a,j]acridine (DBA), 7H-dibenzo[c,g]carbazole (DBC), benzo[b]naphtho[2,1-d]thiophene (BNT) and benzo[b]naphtho[1,2-d]furan (BNF) were selected, based on the results of a previous research project, indicating a lack of toxicity data and a high potential for persistence and bioaccumulation. The solubilities of the NSO-HETs in the test media were determined and turned out to be comparatively low (2.7-317 µg/L) increasing in the following order: DBA < BNT « DBC « BNF. Exposure concentrations during the toxicity tests were quantified with GC-MS and decreased strongly possibly due to sorption or metabolising during the test periods (48-96 h). Therefore, the estimated effect concentrations were related to the mean measured concentrations, as endpoints related to nominal concentrations would have underestimated the toxicity many times over. Within the range of the substance solubilities, BNF affected all test organisms with fish embryos being the most sensitive (fish: EC50 6.7 µg/L, algae: EC10 17.8 µg/L, daphnids: EC50 55.8 µg/L). DBC affected daphnids (EC50 2.5 µg/L,) and algae (EC10 3.1 µg/L), but not fish embryos. The lowest toxicity endpoint was observed for BNT affecting only algae (NOEC 0.556 µg/L) and neither daphnids nor fish embryos. DBA did not show any effects on the tested organisms in the range of the water solubility. However, we would expect effects in long-term toxicity studies to fish and aquatic invertebrates for all substances at lower concentrations, which needs further investigation. All four NSO-HETs were identified in mussels (Mytilus edulis) from the German coasts, in green kale (Brassica oleracea var. acephala) and in freshwater harbor sediment in concentrations between 0.07 and 2 µg/kg, highlighting their relevance as environmental contaminants. There is a need to regulate the four NSO-HETs within the REACH regulation due to their intrinsic properties and their environmental relevance. However, acquisition of additional experimental data appears to be pivotal for a regulation under REACH.