Food and Chemical Toxicology

Colorectal cancer remains a challenging health burden worldwide. This study aimed to assess the potentiality of Strawberry tree honey (STH), a polyphenol-enriched food, to increase the effectiveness of 5-Fluorouracil (5-FU) in adenocarcinoma (HCT-116) and metastatic (LoVo) colon cancer cell lines. The combined treatment reduced cell viability and caused oxidative stress, by increasing oxidative biomarkers and decreasing antioxidant defence, in a more potent way compared to 5-FU alone. The expression of endoplasmic reticulum (ATF-6, XBP-1) and MAPK (p-p38 MAPK, p-ERK1/2) markers were also elevated after the combined treatment, enhancing the cell cycle arrest through the modulation of regulatory genes (i.e., cyclins and CDKs). Apoptotic gene (i.e., caspases) expressions were also increased after the combined treatment, while those of proliferation (i.e., EGFR), cell migration, invasion (i.e., matrix metallopeptidase) and epithelial-mesenchymal transition (N-cadherin, β-catenin) were suppressed. Finally, the combined treatment led cell metabolism towards a quiescent stage, by reducing mitochondrial respiration and glycolysis. In conclusion, this work represents an initial step to highlight the possibility to use STH in combination with 5-FU in the treatment of colon cancer, even if further in vitro an in vivo studies are strongly needed to confirm the possible chemo-sensitizing effects of STH.

The aim of the present work was to evaluate the phenolic profile of the 'Brava' extra virgin olive oil and assess its potential as a "natural adjuvant" in combination with chemotherapy treatment. The total phenol content of the phenolic extracts was 764 mg gallic acid equivalents/kg and the total antioxidant capacity was 2309, 1881 and 2088 μM trolox equivalents/kg determined by Diphenyl-1-picrylhydrazyl free radical method, Ferric Reducing Antioxidant Power and Trolox Equivalent Antioxidant Capacity assay, respectively. Secoiridoids comprised 83% of the total phenolic compounds. The main secoiridoid from oleuropein was the main isomer of oleuropein aglycone (74 mg/kg). The main secoiridoid from ligstroside was the main isomer of ligstroside aglycone (214 mg/kg). These phenolic extracts showed a significant decrease in cell viability on MCF-7 breast cancer cells in a dose and time dependent manner. 48 h-treatments with different concentrations of the extracts induc...

A protracted pro-inflammatory state is the common denominator in the development, progression and complication of the common chronic diseases. Dietary antioxidants represent an efficient tool to counteract this inflammatory state. The aim of the present work was to evaluate the effects of strawberry extracts on inflammation evoked by E. Coli lipopolysaccharide in Human Dermal Fibroblast, by measuring reactive oxygen species production, apoptosis rate, antioxidant enzymes activity, mitochondria functionality and also investigating the molecular pathway involved in inflammatory and antioxidant response. The results demonstrated that strawberry pre-treatment reduced intracellular reactive oxygen species levels, apoptotic rate, improved antioxidant defences and mitochondria functionality in lipopolysaccharide -treated cells. Strawberry exerted these protective activities through the inhibition of the NF-kB signalling pathway and the stimulation of the Nrf2 pathway, with a mechanism AMPK...

Background: Cisplatin (CP) is one of the most effective anti-cancer agents but its use is limited due to renal, hepatic, and intestinal toxicity. Various strategies were made to ameliorate CP-induced damage but were not found suitable for clinical practice. Green tea (Camellia sinensis) has been used for centuries as a medicinal drink. Green Tea (GT) polyphenols have shown strong chemo preventive and chemotherapeutic effects against various pathologies including cancer, diabetes, depression, cardiovascular, and neurological disorders and renal failure. Recently we have shown that GT consumption prevents CP induced nephrotoxicity. Aim: We now hypothesized that GT would protect against CP-induced intestinal and hepatic toxicity by virtue of its antioxidant properties. Methods: CP was co-administered to control and GT-fed male Wistar rats over a period of 25 days. Enzymes of oxidative stress, Brush Border Membrane (BBM), and carbohydrate metabolism were analyzed. Results: CP Suppressed Superoxide Dismutase (SOD) and catalase activities in both intestine and liver. The activity of glucose-6-phosphate dehydrogenase increased whereas that of malic enzyme decreased. However, GT given to CP rats improved the overall metabolism, enhanced antioxidant defense and energy metabolism. The BBM enzymes were differentially altered by GT. Conclusion: In conclusion, Green Tea Ameliorates CP elicited toxicity and oxidative damage by improving antioxidant defense, tissue integrity and energy metabolism.

Modulating effects of high fat fish oil (HFFO) and high fat corn oil (HFCO) diets on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were studied in male F344 rats following 8 weeks of dietary treatment. The incidence of AOM-induced ACF was significantly lower in the proximal colon of rats fed the HFFO diets compared with rats fed the HFCO diets. No differential effects were found on enzyme activities that are involved in metabolic activation and detoxification of AOM. Activities of hepatic P450 IAI and P450 IIBI and hepatic and feacal levels of lipid peroxidation were increased by feeding the HFFO diet. Hepatic GST activity and plasma levels of PGE 2 were significantly lower in rats fed the HFFO diets compared with those fed the HFCO diets. These observations demonstrate that HFFO diets with high levels of n-3 PUFAs are also protective against preneoplastic lesions in the early stages of chemically induced colon carcinogenesis. It seems unlikely from our results that the inhibitory effect of a HFFO diet can be attributed to an altered metabolic activation and detoxification of AOM. Other mechanisms such as oxidative stress or reduction of PGE 2 levels may play an important role in the anticarcinogenic effects of n-3 PUFAs.

Pandemic COVID-19 has a bruthless strength which highly emphasize of all dimension in human life. It made a high turnover in all approach to achieve a better way to minimize the catastrophe. In emergency response the approach for cardiopulmonary arrest are highly debate for ethics and better prognosis and the utmost is safety for medical personnel. COVID-19 is caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is highly contagious. Out of Hospital Cardiac Arrest (OHCA) from French Registry (French National Cardiac Arrest Registry) between march 1st and april 31st 2020 revealed ROSC rate was reduction by six point (ROSC 19.5% vs 25.3%) and D30 survival rate (2.8% vs 6.4%) was halved compared to non COVID 19 period. In the regards of in-hospital cardiac arrest (IHCA) during pandemic, COVID 19 accounts for 16% of IHCA and increased in 30 day mortality 2.3 folds; odd ratio compared with non COVID-19 was 2.27% and adjusted 30day survival were 23.1% in COVID 19, 39.5% in non COVID-19 compared with 36.4% in pre pandemic period. Health workers are the profession with the highest risk of contracting this disease. Resuscitation efforts increase the risk of transmission to health workers for a variety of reasons. To address the issues ILCOR, AHA and ERC have several changes from the recent guideline to confront resuscitation in COVID 19.

Thirdhand smoke (THS) is the toxic residue left behind by tobacco smoke that persists indoors on carpets, furniture, toys, and other items. Children are especially vulnerable to THS exposure due to their hand-to-mouth behaviors, activity near the floor, and developing organs. We provide a scoping narrative review of potential sociodemographic disparities in exposure to THS among children in the United States. Articles were obtained by conducting a search in the PubMed, SCOPUS, and CINAHL databases. Other relevant papers were also reviewed and integrated using narrative synthesis. Studies relevant to THS exposure among 0 to 17-year-olds and conducted in the United States were included. We identified lower socioeconomic status (SES), race, younger age (2-4 years), and living in multiunit housing (MUH) as potential contributors to higher THS exposure risk in children. Lower income was associated with greater THS exposure. THS exposure was higher in Black children, although the number of studies involving them was limited. Examining disparities in exposure and susceptibility to THS can inform future policies to reduce children's environmental exposure to toxic tobacco chemicals in THS. Housing type is likely a primary contributor to exposure disparities, as low-income children are more likely to live in multiunit, rented housing, where tobacco smoke can travel across housing units and where THS residue from former tenants

Species differences exist in terms of drug oxidation activities, which are mediated mainly by cytochrome P450 (P450) enzymes. To overcome the problem of species extrapolation, transchromosomic mice containing a human P450 3A cluster or chimeric mice transplanted with human hepatocytes have been introduced into the human toxicology research area. In this review, drug metabolism and disposition mediated by humanized livers in chimeric mice are summarized in terms of biliary/urinary excretions of phthalate and bisphenol A and plasma clearances of the human cocktail probe drugs caffeine, warfarin, omeprazole, metoprolol, and midazolam. Simulation of human plasma concentrations of the teratogen thalidomide and its human metabolites is possible with a simplified physiologically based pharmacokinetic model based on data obtained in chimeric mice, in accordance with reported clinical thalidomide concentrations. In addition, in vivo nonspecific hepatic protein binding parameters of metabolic...

Food allergy is one of the most common health disorders in the western world. It affects about three per cent of the total population. Food allergy is potentially lethal, and its health impact is higher than that posed by all known chemicals and microbes in food. It is also higher than that of many other disorders and diseases. Additionally, food allergy's economic impact is immense. Consider, for instance, the high number of emergency hospital visits, even hospitalisations, that are due to food-allergy reactions. And despite the food industry's huge investments in preventive measures, between 30 and nearly 50 per cent of all food recalls are allergen-related. To reduce society's food allergy burden, three things must be done. First, we need to adequately manage existing food allergies and exposure to allergens. Second, we must prevent the emergence of allergies to new foods. And, third, cures must be found for food-allergy sufferers, and people must be protected from developing food allergies. During the past 10 years, huge strides have been made. We have better understanding of the risks associated with allergenic foods and proteins, the effects they have on food-allergy sufferers and how we can assess and manage the risks associated with food allergy. TNO is now a world leader in this area. Today, science and technology have reached the stage in which there is a sufficient basis to develop the remaining necessary solutions. In collaboration with universities, clinical centres, patient organisations, authorities and the food industry, the multidisciplinary and non-profit TNO Shared Research Program Food Allergy is aiming high. It intends to dispel remaining existing hurdles and realise necessary innovations to keep us firmly on course Towards a Food-Allergy-Free World. And all by 2030. Food allergy causes substantial distress. Affecting about three per cent of the total population, it is one of the most common health disorders in the western world 1,2 . It has a more detrimental effect on health than chemicals and microbes in food. Especially when one takes into account the enormous impact it has on the lives of food-allergy sufferers and their environment . In loss of Disability Adjusted Life Years (DALYs), it is estimated that the health impact of food allergy exceeds, for example, that of skin cancer, Parkinson's disease or cardiac arrest. Loss in DALYs for food allergy is approximately the same as for prostate cancer, asthma and rheumatoid arthritis . In a recent prospective study in the Netherlands, for every 100 people affected by food allergies, there were four emergency hospital visits and 0.6 hospitalisations per year 5 . Considering the total number of food-allergy sufferers in the Netherlands (approximately 500,000), these results suggest tens of thousands of emergency hospital visits and several thousand hospitalisations per year in the Netherlands. Compare this with the fact there are less than 100 hospitalisations per year due to food infections in the Netherlands 6 . Food companies invest heavily in preventive measures and risk management. But despite these investments, several studies have shown that between 30 and almost 50 per cent of all food recalls are allergen-related 7 .

The current allergenicity assessment of novel proteins is based on the EFSA GMO guidance. Recently, EFSA launched a new guidance document on allergenicity assessment of GM plants (2017). This document describes, amongst other topics, the new scientific and regulatory developments on in vitro protein digestibility tests. The EFSA GMO Panel stated that for in vitro protein digestibility tests, additional investigations are needed before any additional recommendation in the form of guidance can be provided. To this end, an interim phase is considered necessary to evaluate the revisions to the in vitro gastrointestinal digestion test, proposed by EFSA. This prompted the establishment of a joint workshop through two COST Action networks: COST Action ImpARAS and COST Acton INFOGEST. In 2017, a workshop was organised to discuss the relevance of digestion in allergenicity risk assessment and how to potentially improve the current methods and readouts. The outcome of the workshop is that there is no rationale for a clear readout that is predictive for allergenicity and we suggest to omit the digestion test from the allergenicity assessment strategy for now, and put an effort into filling the knowledge gaps as summarized in this paper first.

Many food innovations rely on the introduction and use of new or modified proteins. New or modified food proteins may lead to major health risks due to their inherent potential to cause food allergy. Currently, the pre-market allergenicity assessment for new or modified food proteins and protein sources relies on methods for identifying allergenic hazards based on characteristics of known allergens. However, there is no general consensus on the allergenicity parameters to use and the criteria that should apply for the evaluation and decisions to be made. In this paper, we propose that the strategy for allergenicity risk assessment of new or modified food proteins and the methodologies applied should be governed by the risk management questions to be answered, reflected in the information needed by risk managers to enable

Food processing can have many beneficial effects. However, processing may also alter the allergenic properties of food proteins. A wide variety of processing methods is available and their use depends largely on the food to be processed. In this review the impact of processing (heat and non-heat treatment) on the allergenic potential of proteins, and on the antigenic (IgG-binding) and allergenic (IgE-binding) properties of proteins has been considered. A variety of allergenic foods (peanuts, tree nuts, cows' milk, hens' eggs, soy, wheat and mustard) have been reviewed. The overall conclusion drawn is that processing does not completely abolish the allergenic potential of allergens. Currently, only fermentation and hydrolysis may have potential to reduce allergenicity to such an extent that symptoms will not be elicited, while other methods might be promising but need more data. Literature on the effect of processing on allergenic potential and the ability to induce sensitisation is scarce. This is an important issue since processing may impact on the ability of proteins to cause the acquisition of allergic sensitisation, and the subject should be a focus of future research. Also, there remains a need to develop robust and integrated methods for the risk assessment of food allergenicity.

High sodium chloride (NaCl) intake is associated with health risks. NaCl may be replaced by potassium chloride (KCl) to decrease sodium intake. However, increased potassium may also have negative health effects. We conducted a benefit and risk assessment of increasing potassium by ratios of 30:70, 50:50, 70:30 (weight % K+: weight % Na+) in children, adolescents and adults in Norway, using intake data from national food consumption surveys and available literature on potassium health effects. An intake of at least 3.5 g/day of potassium decreases risk of stroke and hypertension, and this level was used in the benefit assessment of the healthy population. Three g/day of potassium added to mean food intake is assumed safe, and these levels were used in the risk assessment. Not all persons reached the protective level of potassium, and increasing numbers exceeded the safe levels, in these scenarios. In addition, elderly above 85 years and infants below one year of age, as well as sever...

4,4′-Methylenedianiline (MDA) is used as a hardener in the manufacture of plastics and polyurethanes. MDA has been classified as a carcinogen in animals and is a suspected human carcinogen. Assuming that MDA would yield similar DNA adducts to other arylamines, we synthesized the following C-8 guanine adducts: N′-acetyl-N-(deoxyguanosin-8-yl)-MDA, N-(deoxyguanosin-8-yl)-MDA, N-(deoxyguanosin-8-yl)-4MA, and their corresponding 3′-monophosphate derivatives. We developed methods to identify these adducts of MDA in liver DNA using 32 P-postlabeling, HPLC, and GC-MS techniques. Liver DNA was obtained from rats treated with radiolabeled MDA (1.11 and 116.5 µmol/kg body weight). The total radioactivity bound to the DNA corresponded to 0.06 and 2.7 adducts per 10 7 nucleotides [covalent binding index (CBI ) (µmol of adduct per mol of nucleotide)/(mmol of compound per kg body weight)) of 1.05 and 2.3]. This DNA-binding potency is in the range of weakly genotoxic compounds. The liver DNA was analyzed for the presence of the synthesized adducts by the following methods: (I) HPLC analysis of nucleotides and purines after enzymatic and acid hydrolysis, and (II) 32 P-postlabeling after enzymatic hydrolysis. The major adducts found in vivo did not correspond to the synthesized standards. Further work was carried out to determine the structure of the unidentified adducts. It was possible to release MDA and MDA-d 4 from DNA of rats dosed with MDA and/or MDA-d 4 and from the synthesized adducts using strong base hydrolysis. Liver of two female Wistar rats given 500 µmol/kg MDA‚2HCl was hydrolyzed in 0.1 M NaOH overnight at 110 °C. GC-MS analysis of the heptafluorobutyric anhydride derivatized dichloromethane extracts detected 428 ( 40 fmol of MDA/mg of DNA. In the control animals no MDA was found. The experiment was repeated with livers from animals dosed 500 µmol/kg MDA-d 4 ‚2DCl. In these rats 488 ( 19 fmol MDA-d 4 was found to be bound at liver DNA. Taking into account a 68% yield of the method, the CBI found in these cases was 0.82 and 1.0, respectively.

Contrariamente a lo que se ha venido diciendo respecto a que el Maestro Saint Germain ha dejado una prohibición de divulgación de su enseñanza tenemos el gusto de referir al estudiante al Capítulo N. ° 29, tercer párrafo, que dice textualmente:

Contrariamente a lo que se ha venido diciendo respecto a que el Maestro Saint Germain ha dejado una prohibición de divulgación de su enseñanza tenemos el gusto de referir al estudiante al Capítulo N. ° 29, tercer párrafo, que dice textualmente:

Free radicals and activated oxygen radical species are generated as a result of aerobic metabolism. Imbalance, if any in the antioxidant defense system against free radicals can degrade biomolecules inside the living system. In this present study, antioxidant arbitrated protective activity of Mesua ferrea L. is reported on induced oxidative damage in erythrocytes, Hb and DNA. Both, MCE (M. ferrea chloroform extract) and MEE (M. ferrea ethanol extract) exhibited significant antioxidant activity while MEE showed >90% protection to erythrocytes, Hb and DNA by virtue of high total phenolics (1.005 ± 0.005 mg EGA mg -1 ) and total flavonoids (514.8 g mg -1 ) whereas MCE showed <90% but >70% antioxidant protective activity probably due to 0.596 ± 0.002 mg EGA mg -1 total phenolics and 275.9 g EQ mg -1 total flavonoid content. It indicates that M. ferrea Linn. possesses significant protective activity against induced oxidative stress by acting as a strong antioxidant and potential electro-catalyst during the electrochemical oxidation of H 2 O 2 . Furthermore, HPLC of MCE and MEE revealed well known various good antioxidant molecules such as gallic acid, ellagic acid, coumaric acid, vanillic acid, rutin, quercetin, myricetin and kaempferol. Thus, M. ferrea Linn. bark was found to be having a good antioxidant property.

1. Ms.C of Microbiology, Department of Microbiology, Karaj Branch, Islamic Azad University, Karaj, Iran. 2.Professor of Mycology, Department of Microbiology, Karaj Branch, Islamic Azad University, Karaj, Iran. 3.Associate Professor of Biology, Department of Biology, Karaj Branch, Islamic Azad University, Karaj, Iran. 4.Ph.D of Microbiology, Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.

In recent times, machine learning has become increasingly prominent in predictive toxicology as it has shifted from in vivo studies towards in silico studies. Currently, in vitro methods together with other computational methods such as QSAR modelling and ADME calculations are being used. An overview of machine learning and its applications in predictive toxicology is presented here, including support vector machines (SVMs), Random forest (RF) and decision trees (DTs), neural networks, regression models, Naive Bayes, k-nearest neighbours (kNNs), and ensemble learning. The recent successes of these machine learning methods in predictive toxicology are summarized and a comparison of some models used in predictive toxicology is presented. In predictive toxicology SVMs, RF and DTs are the dominant machine learning methods due to the characteristics of the data available. Lastly, this review describes the current challenges facing the use of machine learning in predictive toxicology and offers insights into the possible areas of improvement in the field.

In recent times, machine learning has become increasingly prominent in predictive toxicology as it has shifted from in vivo studies towards in silico studies. Currently, in vitro methods together with other computational methods such as QSAR modelling and ADME calculations are being used. An overview of machine learning and its applications in predictive toxicology is presented here, including support vector machines (SVMs), Random forest (RF) and decision trees (DTs), neural networks, regression models, Naive Bayes, k-nearest neighbours (kNNs), and ensemble learning. The recent successes of these machine learning methods in predictive toxicology are summarized and a comparison of some models used in predictive toxicology is presented. In predictive toxicology SVMs, RF and DTs are the dominant machine learning methods due to the characteristics of the data available. Lastly, this review describes the current challenges facing the use of machine learning in predictive toxicology and offers insights into the possible areas of improvement in the field.

A variety of imaging and analytical methods have been developed to study nanoparticles in cells. Each has its benefits, limitations, and varying degrees of expense and difficulties in implementation. High-resolution analytical scanning transmission electron microscopy (HRSTEM) has the unique ability to image local cellular environments adjacent to a nanoparticle

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This work examines the antitumor activity of an isomeric mixture (1), composed of the limonoids meliartenin and its interchangeable isomer 12-hydroxyamoorastatin. The results obtained showed that 1 displayed outstanding cytotoxic activity against CCRF-CEM, K562, A549 and HCT116 cells, with a highly selective effect on the latter, with an IC50 value of 0.2 μM. Based on this finding, HCT116 cells were selected to study the mechanism of action of 1. Cell cycle analysis revealed that 1 induced sustained arrest in the S-phase, which was followed by the triggering of apoptotic cell death and reduced clonogenic capacity. This cytotoxicity was seen to be preceded by the upregulation of the tumor suppressor p53 and its target effector p21. In addition, it was found that p53 expression was required for efficient cell death induction, and thus that the toxicity of 1 relies mainly on p53-dependent mechanisms. Taken together, these findings position 1 as a potent antitumor agent, with potential ...

Polycyclic Aromatic Hydrocarbons (PAHs) is a group of about 200 organic compounds formed by two or more aromatic condensed rings, considered as significant food processing contaminants, characterized by mutagenic and carcinogenic properties. In particular, meat cooking can lead to the formation of these harmful compounds. The maximum residue levels for the sum of 4 PAHs and for benzo[a]pyrene (BaP) in food products are established in Europe by the Regulation (EU) No. 915/2023.
In this study, six different cooking treatments were tested on four different types of meat, such as loin, neck, chicken and bovine hamburger. Four of these treatments were also carried out prolonging the cooking time to verify PAHs possible increase. The analytical determination of 4 PAHs (benzo[a]anthracene (BaA), chrysene (Chry), benzo[b]fluoranthene (BbF) and benzo[a]pyrene) was obtained using a fully validated and accredited method by QuEChERs dispersive solid phase extraction coupled to GC-MS/MS. A study on the chromatographic separation of benzofluoranthene isomers was also carried out.
The overall evaluations have highlighted that some characteristics of various cooking techniques can influence the formation of PAHs, particularly cooking time and oil use.

Bioconcentration refers to the process of uptake and buildup of chemicals in living organisms. Experimental measurement of bioconcentration factor (BCF) is time-consuming and expensive, and is not feasible for a large number of chemicals of regulatory concern. Quantitative structure-activity relationship (QSAR) models are used for estimating BCF values to help in risk assessment of a chemical. This paper presents the results of a QSAR study conducted to address an important problem encountered in the prediction of the BCF of highly hydrophobic chemicals. A new QSAR model is derived using a dataset of diverse organic chemicals previously tested in a United States Environmental Protection Agency laboratory. It is noted that the linear relationship between the BCF and hydrophobic parameter, i.e., calculated octanol-water partition coefficient (ClogP), breaks down for highly hydrophobic chemicals. The parabolic QSAR equation, log BCF = 3.036 ClogP À 0.197 ClogP 2 À 0.808 MgVol (n = 28, r 2 = 0.817, q 2 = 0.761, s = 0.558) (experimental log BCF range = 0.44-5.29, ClogP range = 3.16-11.27), suggests that a non-linear relationship between BCF and the hydrophobic parameter, along with inclusion of additional molecular size, weight and/or volume parameters, should be considered while developing a QSAR model for more reliable prediction of the BCF of highly hydrophobic chemicals.

Induction of programmed cell death, mainly apoptosis (lipoapoptosis) is a major cellular consequence of the lipotoxicity, a harmful effect resulting from the overload of lipids. Both Endoplasmic reticulum (ER) stress and autophagy have been suggested to play important role in the regulation of lipoapoptosis. However, the exact mechanisms underlying lipoapoptosis remain unclear. In the present study, we aimed to investigate the functional role of Bax/Bak in lipoapoptosis using mouse embryonic fibroblasts (MEFs) cell culture model. Results showed that palmitate induced caspase-dependent apoptosis in wild-type Bax/Bak MEF cells, whereas a caspaseindependent cell death was induced by palmitate in Bax/Bak knockout MEF cells, suggesting requirement of Bax/Bak in palmitate-induced caspase activation. More importantly, we found that the status of Bax/Bak is a determinant that governs the decision between the pro-survival or pro-death function of autophagy in response to palmitate exposure, and Bax/Bak is required for palmitate-induced activation of endoplasmic reticulum (ER) stress and subsequently ER stress-mediated apoptosis. The findings of the present study provided novel insights into understanding the mechanisms involved in the regulation of palmitate-induced lipoapoptosis.

Induction of programmed cell death, mainly apoptosis (lipoapoptosis) is a major cellular consequence of the lipotoxicity, a harmful effect resulting from the overload of lipids. Both Endoplasmic reticulum (ER) stress and autophagy have been suggested to play important role in the regulation of lipoapoptosis. However, the exact mechanisms underlying lipoapoptosis remain unclear. In the present study, we aimed to investigate the functional role of Bax/Bak in lipoapoptosis using mouse embryonic fibroblasts (MEFs) cell culture model. Results showed that palmitate induced caspase-dependent apoptosis in wild-type Bax/Bak MEF cells, whereas a caspaseindependent cell death was induced by palmitate in Bax/Bak knockout MEF cells, suggesting requirement of Bax/Bak in palmitate-induced caspase activation. More importantly, we found that the status of Bax/Bak is a determinant that governs the decision between the pro-survival or pro-death function of autophagy in response to palmitate exposure, and Bax/Bak is required for palmitate-induced activation of endoplasmic reticulum (ER) stress and subsequently ER stress-mediated apoptosis. The findings of the present study provided novel insights into understanding the mechanisms involved in the regulation of palmitate-induced lipoapoptosis.

As part of a survey conducted by the Central Agricultural Office of Hungary, 67 food samples including beverages were taken from 57 food industrial and catering companies, 75% of them being small and medium-sized enterprises (SMEs). Moreover, 40% of the SMEs were micro entities. Water used for food processing was simultaneously sampled. The arsenic (As) content of solid food stuff was determined by hydride generation atomic absorption spectrometry after dry ashing. Food stuff with high water content and water samples were analyzed by inductively coupled plasma mass spectrometry. The As concentration exceeded 10 μg/L in 74% of the water samples taken from SMEs. The As concentrations of samples with high water content and water used were linearly correlated. Estimated As intake from combined exposure to drinking water and food of the population was on average 40% of the daily lower limit of WHO on the benchmark dose for a 0.5% increased incidence of lung cancer (BMDL 0.5 ) for As. Five settlements had higher As intake than the BMDL 0.5 . Three of these settlements are situated in Csongrád county and the distance between them is less than 55 km. The maximum As intake might be 3.8 µg/kg body weight.

Cisplatin (CP) is an effective chemotherapeutic agent widely used in the treatment of many malignant tumours. However, its therapeutic utility is limited by dose dependent nephrotoxicity. Several agents/strategies have attempted to prevent CP nephrotoxicity but were not found suitable for clinical practice. Dietary flaxseed oil (FXO), a rich source of omega-3 fatty acids has been shown to prevent/reduce the progression of certain types of cardiovascular and renal disorders. The protective effect of FXO on CP induced nephrotoxic and other deleterious effects was investigated. Rats were prefed experimental diets for 10 days and then received a single dose of CP (6 mg/kg body weight) intraperitoneally while still on diet. Serum/urine parameters, enzymes of brush border membrane (BBM), oxidative stress and carbohydrate metabolism in rat kidney were analyzed. CP nephrotoxicity was recorded by increased serum creatinine and blood urea nitrogen. CP decreased the activities of metabolic enzymes, antioxidant defense system and BBM enzymes. In contrast, FXO alone increased enzyme activities of carbohydrate metabolism and brush border membrane. FXO feeding to CP treated rats markedly enhanced resistance to CP-elicited deleterious effects. Dietary FXO supplementation ameliorated CP induced specific metabolic alterations and oxidative damage due to its intrinsic biochemical antioxidant properties.

Solanum nigrum L. (SNL) has been traditionally used as a herbal plant, whose fruit is believed to have anti-tumor properties, although the mechanism for the activity remains to be elucidated. In this study, we prepared an ethanol extract from ripe fruits of SNL and investigated the mechanism involved in its growth-inhibitory effect on MCF-7 human breast cancer cells. Results from proliferation assay using tritium uptake showed that the proliferative capacity of MCF-7 cells was strongly suppressed in the presence of SNL ethanol extract. This was further confirmed through MTT assay and trypan blue exclusion experiments, which showed a very close correlation between the SNL extract concentration and the surviving cell numbers. The SNL extract-mediated suppression of cell growth was verified to be apoptotic, based on the appearance of DNA laddering, increase in DNA fragmentation, and low fluorescence intensity in nuclei after propidium iodide staining of the cells. Furthermore, the SNL extract was revealed to be a potential scavenger of hydroxyl radicals and DPPH radicals rather than superoxide anions. Collectively, our findings suggest that SNL fruit extract could be used as an anti-oxidant and cancer chemo-preventive material.

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Recently, steps have been taken to further developments toward increasing gamma-linolenic acid (GLA) concentration and lowering costs in plant seed oils using transgenic technology. Through identification and expression of a fungal delta-6 desaturase gene in the high linoleic acid safflower plant, the seeds from this genetic transformation produce oil with >40% GLA (high GLA safflower oil (HGSO)). The aim of the study was to compare the effects of feeding HGSO to a generally recognized as safe source of GLA, borage oil, in a 90 day safety study in rats. Weanling male and female Sprague-Dawley rats were fed a semi-synthetic, fat free, pelleted diet (AIN93G) supplemented with a 10% (wt/wt) oil blend containing HGSO or borage oil, with equivalent GLA levels. Results demonstrated that feeding diets containing HGSO or borage oil for 90 days had similar biologic effects with regard to growth characteristics, body composition, behavior, organ weight and histology, and parameters of hematology and serum biochemistries in both sexes. Metabolism of the primary n-6 fatty acids in plasma and organ phospholipids was similar, despite minor changes in females. We conclude that HGSO is biologically equivalent to borage oil and provides a safe alternative source of GLA in the diet.

Banana Xanthomonas wilt (BXW) disease threatens banana production and food security throughout East Africa. Natural resistance is lacking among common cultivars. Genetically modified (GM) bananas resistant to BXW disease were developed by inserting the hypersensitive response-assisting protein (Hrap) or/and the plant ferredoxin-like protein (Pflp) gene(s) from sweet pepper (Capsicum annuum). Several of these GM banana events showed 100% resistance to BXW disease under field conditions in Uganda. The current study evaluated the potential allergenicity and toxicity of the expressed proteins HRAP and PFLP based on evaluation of published information on the history of safe use of the natural source of the proteins as well as established bioinformatics sequence comparison methods to known allergens (www. AllergenOnline.org and NCBI Protein) and toxins (NCBI Protein). The results did not identify potential risks of allergy and toxicity to either HRAP or PFLP proteins expressed in the GM bananas that might suggest potential health risks to humans. We recognize that additional tests including stability of these proteins in pepsin assay, nutrient analysis and possibly an acute rodent toxicity assay may be required by national regulatory authorities.

A study was conducted to assess the effects of ribofiavin deficiency and riboflavin supplementation on carcinogen-DNA binding. After 12 wk on a riboflavin-sufficient or a riboflavin-deficient diet male Wistar rats were administered 3H-labelled benzo[a]pyrene (BP) ip. [3H]BP was given either at a uniform dose of 450 #Ci/rat irrespective of body weight or at a dose adjusted to body weight. After 17 hr the animals were killed, various organs were dissected and the level of [3H]BP bound to DNA was quantified in organs that are known to be the seats of drug metabolism (i.e. the liver, lungs and intestinal mucosa). In a separate experiment, the effect of riboflavin supplementation on BP-DNA binding was also investigated. When [3H]BP was administered at 450 #Ci/rat, BP-DNA binding was markedly increased in the livers and intestinal mucosae of the pair-fed and deficient groups compared with controls. With the administration of [3 H]BP adjusted to body weight, no differences in BP-DNA binding between groups were observed in any tissue. However, on administration of riboflavin there was a decrease in the level of [3 H]BP bound to DNA in almost all tissues, especially in the lungs, where the reduction was significant. The results suggest that undernutrition/riboflavin deficiency may increase the risk of carcinogenesis by way of an increase in carcinogen binding, which however can be reversed by riboflavin supplementation.

Anatomical and physiological parameters of the gastrointestinal (GI) tract dramatically aect the rate and extent of absorption of ingested compounds. These parameters must be considered by nutritionists, pharmacologists and toxicologists when describing or modeling absorption. Likewise, interspecies extrapolation (e.g. from rat to human) requires species-to-species comparison of these parameters. The present paper (1) describes the alimentary canal and the barrier to absorption; (2) relates the major sites of absorption; (3) compares the dimensions and surface areas of human and rat intestinal tracts; (4) discusses motility of the gut and transit times through regions of the alimentary canal; (5) explains how luminal contents are altered by physical, chemical and metabolic processes; and (6) describes the ¯ow of blood and lymph from the GI tract to the systemic circulation, including the enterohepatic circulation. Despite strong morphological similarities between humans and rats at the microscopic level, gross anatomical dierences in the relative absorptive surface areas provide a basis for concluding that the human GI tract is capable of absorbing materials faster and to a greater extent than that of the rat. Dierences in the environment of the GI lumen of the two species make it possible to infer which substances are more likely to be present in a dissolved/non-ionized state for each species. Taken together, these dierences may be of sucient magnitude to alter the assessment of risks/bene®ts for a given compound when those risks/bene®ts are based on interspecies extrapolations.

Camu-camu (Myrciaria dubia) pulp, seeds, and skin are widely known because of their nutritional properties. However, the seed coat has never been studied as a source of bioactive compounds. Herein, we characterized the phenolic composition, the antioxidant activity, and inhibition of angiotensin-converting enzyme (ACE) of three different extracts (water, propanone, and ethanol) from this residue and assessed the structure-activity using bivariate and multivariate statistical approaches. Phenolic acids and flavonoids were quantified by high-performance liquid chromatography while the ferric reducing antioxidant power (FRAP), inhibition of lipid peroxidation using egg yolk and Wistar rat brain, scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH • ) radical, Folin-Ciocalteu reducing capacity (FCRC), and the inhibition of angiotensin-converting enzyme (ACE) by the extracts were also analyzed. t-Resveratrol was found in camu-camu seed coat for the first time. The aqueous extract had the highest total phenolic content, FRAP, DPPH • , FCRC, and inhibition of lipid oxidation using both chemical and biological assays, while the propanone extract showed the opposite behavior but it presented higher in vitro antihypertensive activity. The ethanolic extract exhibited intermediate values for the responses. The association between chemical composition and the functional properties of the camu-camu seed coat extracts were revealed using correlation analysis and principal component analysis.

Camu-camu (Myrciaria dubia) pulp, seeds, and skin are widely known because of their nutritional properties. However, the seed coat has never been studied as a source of bioactive compounds. Herein, we characterized the phenolic composition, the antioxidant activity, and inhibition of angiotensin-converting enzyme (ACE) of three different extracts (water, propanone, and ethanol) from this residue and assessed the structure-activity using bivariate and multivariate statistical approaches. Phenolic acids and flavonoids were quantified by high-performance liquid chromatography while the ferric reducing antioxidant power (FRAP), inhibition of lipid peroxidation using egg yolk and Wistar rat brain, scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH • ) radical, Folin-Ciocalteu reducing capacity (FCRC), and the inhibition of angiotensin-converting enzyme (ACE) by the extracts were also analyzed. t-Resveratrol was found in camu-camu seed coat for the first time. The aqueous extract had the highest total phenolic content, FRAP, DPPH • , FCRC, and inhibition of lipid oxidation using both chemical and biological assays, while the propanone extract showed the opposite behavior but it presented higher in vitro antihypertensive activity. The ethanolic extract exhibited intermediate values for the responses. The association between chemical composition and the functional properties of the camu-camu seed coat extracts were revealed using correlation analysis and principal component analysis.

Biomarkers of exposure and effect were assessed in 40 male Sprague-Dawley rats injected intravenously with 40 µmol/kg of benzo(a)pyrene (BaP) to determine which biomarkers are more representative of BaP-induced DNA damage in lung. Lung, liver, blood, and urine were collected at t ) 2, 4, 8, 16, 24, 33, 48, 72, and 360 h postdosing. Specific BaP-diol epoxide (BPDE)-DNA adducts, 8-hydroxy-7,8dihydro-2′-deoxyguanosine (8-OHdGuo), were measured in lung, liver, and mononucleated blood cells by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). Urinary 8-OHdGuo and 8-hydroxy-7,8-dihydroguanosine (8-OHGuo) were also determined by HPLC-MS/MS, and urinary 3-hydroxybenzo(a)pyrene was measured by HPLC/fluorescence. Between 2 and 72 h postdosing, BPDE-DNA adducts were significantly increased in lung, liver, and mononucleated blood cells of BaP-treated rats as compared to controls, with the highest levels found in lung. 8-OHdGuo levels also increased in lung of BaP-treated rats with values reaching statistical significance at 2, 8, and 16 h postinjection. No influence of BaP treatment was found on 8-OHdGuo and 8-OHGuo urinary excretions. BPDE-DNA adducts in lung were strongly correlated to urinary 3-OHBaP (r ) 0.936 and p < 0.001) and to a lesser extent to blood BPDE-DNA adducts (r ) 0.636 and p < 0.001), the latter of which were correlated to each other (r ) 0.573 and p ) 0.002). Urinary 3-OHBaP and BPDE-DNA adducts in mononucleated blood cells appear as relevant biomarkers of BaP genotoxic exposure and are highly promising for health risk assessment in humans.

Exposures to plant protection products (PPPs) are assessed using risk analysis methods to protect public health. Traditionally, single sources, such as food or individual occupational sources, have been addressed. In reality, individuals can be exposed simultaneously to multiple sources. Improved regulation therefore requires the development of new tools for estimating the population distribution of exposures aggregated within an individual. A new aggregate model is described, which allows individual users to include as much, or as little, information as is available or relevant for their particular scenario. Depending on the inputs provided by the user, the outputs can range from simple deterministic values through to probabilistic analyses including characterisations of variability and uncertainty. Exposures can be calculated for multiple compounds, routes and sources of exposure. The aggregate model links to the cumulative dietary exposure model developed in parallel and is implemented in the web-based software tool MCRA. Case studies are presented to illustrate the potential of this model, with inputs drawn from existing European data sources and models. These cover exposures to UK arable spray operators, Italian vineyard spray operators, Netherlands users of a consumer spray and UK bystanders/residents. The model could also be adapted to handle non-PPP compounds.

Dendritic cells (DC) are known to play a major role during contact allergy induced by contact sensitizers (CS). Our previous studies showed that Nrf2 was induced in DC and controlled allergic skin inflammation in mice in response to chemicals. In this work, we raised the question of the role of Nrf2 in response to a stress provoked by chemical sensitizers in DC. We used two well-described chemical sensitizers, dinitrochlorobenzene (DNCB) and cinnamaldehyde (CinA), known to have different chemical reactivity and mechanism of action. First, we performed a RT-qPCR array showing that CinA was a higher inducer of immune and detoxification genes compared to DNCB. Interestingly, in the absence of Nrf2, gene expression was dramatically affected in response to DNCB but was slightly affected in response to CinA. These observations prompted us to study DC&#39;s cell death in response to both chemicals. DNCB and CinA increased apoptotic cells and decreased living cells in the absence of Nrf2. T...

Conventional sample preparation methods for liquid chromatography-mass spectrometry (LC-MS/MS) are time consuming, laborious, expensive, and require large volumes of solvent for extraction and cleanup. We developed and validated a micro liquid-liquid extraction (MLLE) sample preparation method for LC-MS/MS analysis of thiacloprid insecticide residues in green onion. MLLE is a simple, rapid, and cost-effective method that uses less extraction solvent and does not require adsorbents or the cleanup step. The samples are homogenized with dichloromethane, centrifuged, the solvent evaporated to dryness and the residue is reconstituted with fivefold of acetonitrile; thus, the method is ecologically safer and low cost. The limit of quantification was 0.01 mg/kg. Method efficiency for MLLE was compared with the conventional QuEChERS sample preparation. MLLE exhibited good linearity (correlation coefficient, [ 0.99). The average recovery ranged from 97.2 to 101.5%. Intra-and inter-day repeatabilities were 9.7 and 13.8%, respectively. Matrix effects were nonsignificant (suppression, 2.2%). The MLLE method was used to quantify the residual levels and rate of dissipation of thiacloprid in field trial green onion. The dissipation of thiacloprid fitted first-order kinetics, with half-lives of 1.92 and 2 days after application of the recommended dose (48 g a.i/ha) and double the recommended dose (96 g a.i/ha). Thiacloprid residues were below the limit of detection in green onion samples analyzed 14 days after spraying with either dose. Based on the maximum residue limit, a waiting period of 9 days is recommended. From Egyptian consumers' point of view, the consumption of onion seems quite safe.

8,263-2711 have shown that microsomes oxidize acetonitrile to cyanide. Treatment of rats with inducers of cytochrome P-450 IIEl such as pyrazole, 4-methylpyrazole, and ethanol resulted in a 4-to &fold increase in cyanide production from acetonitrile by isolated microsomes. Phenobarbital treatment had a small stimulatory effect, whereas 3-methylcholanthrene treatment decreased microsomal oxidation of acetonitrile. Pyrazole treatment increased V,, per milligram of microsomal protein and per nanomole of P-450 but did not affect the apparent k, for acetonitrile, whereas the 4-methylpyrazole treatment increased V,, and the apparent affinity for acetonitrile. Cyanide production was inhibited by carbon monoxide as well as by substrates and compounds that interact with the P-450 IIEl isozyme such as ethanol, 2-butanol, DMSO, and 4-methylpyrazole. Oxidation of acetonitrile to cyanide by microsomes from rats treated with pyrazole or 4-methylpyrazole was nearly completely inhibited by anti-P-450 3a IgG. These results implicate a role for P-450 in the oxidation of acetonitrile to cyanide and suggest that P-450 IIEl may be an especially effective catalyst for this oxidation. Acetonitrile oxidation was not affected by hydroxyl radical scavengers or by desferrioxamine, indicating no role for hydroxyl radicals in the overall mechanism. Azide, an inhibitor of catalase, completely blocked cyanide production from acetonitrile by all microsomal preparations; added catalase overcame the azide inhibition. Formate, a substrate for the peroxidatic activity of catalase, also blocked microsomal oxidation of acetonitrile. These results implicate a role for catalase in the microsomal oxidation of acetonitrile; however, catalase-H202 did not oxidize acetonitrile to cyanide under conditions in which other peroxidatic substrates such as ethanol were oxidized. A reconstituted system containing P-450 IIEl purified from pyrazole-treated rats oxidized acetonitrile to cyanide; the presence of catalase was required for this production of cyanide. These results suggest that the overall oxidation of acetonitrile to cyanide is mediated by a two-step process. The first step involves oxidation of acetonitrile by cytochrome P-450 to a hydroxylated metabolite. P-450 IIEl is especially effective as a catalyst for this step. The second step involves peroxidation of this metabolite by catalase-H202, with the subsequent release of cyanide. Ethanol, which has been found useful in preventing toxicity of nitriles, may act by competing with acetonitrile for oxidation by P-450 IIEl as well as by acting as a competitive substrate for the peroxidatic activity of catalase-H202.

8,263-2711 have shown that microsomes oxidize acetonitrile to cyanide. Treatment of rats with inducers of cytochrome P-450 IIEl such as pyrazole, 4-methylpyrazole, and ethanol resulted in a 4-to &fold increase in cyanide production from acetonitrile by isolated microsomes. Phenobarbital treatment had a small stimulatory effect, whereas 3-methylcholanthrene treatment decreased microsomal oxidation of acetonitrile. Pyrazole treatment increased V,, per milligram of microsomal protein and per nanomole of P-450 but did not affect the apparent k, for acetonitrile, whereas the 4-methylpyrazole treatment increased V,, and the apparent affinity for acetonitrile. Cyanide production was inhibited by carbon monoxide as well as by substrates and compounds that interact with the P-450 IIEl isozyme such as ethanol, 2-butanol, DMSO, and 4-methylpyrazole. Oxidation of acetonitrile to cyanide by microsomes from rats treated with pyrazole or 4-methylpyrazole was nearly completely inhibited by anti-P-450 3a IgG. These results implicate a role for P-450 in the oxidation of acetonitrile to cyanide and suggest that P-450 IIEl may be an especially effective catalyst for this oxidation. Acetonitrile oxidation was not affected by hydroxyl radical scavengers or by desferrioxamine, indicating no role for hydroxyl radicals in the overall mechanism. Azide, an inhibitor of catalase, completely blocked cyanide production from acetonitrile by all microsomal preparations; added catalase overcame the azide inhibition. Formate, a substrate for the peroxidatic activity of catalase, also blocked microsomal oxidation of acetonitrile. These results implicate a role for catalase in the microsomal oxidation of acetonitrile; however, catalase-H202 did not oxidize acetonitrile to cyanide under conditions in which other peroxidatic substrates such as ethanol were oxidized. A reconstituted system containing P-450 IIEl purified from pyrazole-treated rats oxidized acetonitrile to cyanide; the presence of catalase was required for this production of cyanide. These results suggest that the overall oxidation of acetonitrile to cyanide is mediated by a two-step process. The first step involves oxidation of acetonitrile by cytochrome P-450 to a hydroxylated metabolite. P-450 IIEl is especially effective as a catalyst for this step. The second step involves peroxidation of this metabolite by catalase-H202, with the subsequent release of cyanide. Ethanol, which has been found useful in preventing toxicity of nitriles, may act by competing with acetonitrile for oxidation by P-450 IIEl as well as by acting as a competitive substrate for the peroxidatic activity of catalase-H202.

Since the emergence of acute respiratory syndrome coronavirus (SARS-CoV-2, the virus that causes COVID-19), which was first reported in China in December 2019 and later declared a global pandemic by the World Health Organization on March 11, 2020, nearly 51 million cases of COVID-19 have been reported worldwide, with over 333446 deaths last year. Aside from the acute mortality triggered by COVID-19, there are increasing concerns about the impact of the pandemic on health facilities. Patients may have been hesitant to phone emergency medical services (EMS) or go to emergency rooms due to lockdown and movement restrictions enforced in some nations, as well as the fear of contamination in hospitals, resulting in inadequate health care and delays. Furthermore, entire healthcare systems have been restructured to deal with this enormous influx of people with a highly contagious new disease. Routine medical activities, such as scheduled hospitalizations and consultations, were postponed in order to focus on COVID-19 care and prevent exposing stable patients to the danger of contamination at the hospital. Overall, the indirect impacts of the COVID-19 pandemic could have a negative effect on human health. Healthcare workers suffer from occupational stress during the pandemic, which, in turn, may lead to distress, burnout, psychosomatic problems, and cardiac arrest during their interventions in the treatment of hospitalized patients. Now with the death of medical residents in a row, many doctors and residents are using social media to share their bitter experiences with everyone with the hashtag ''Tell a resident ''

Carbon nanotubes (CNTs) are the most studied allotropic form of carbon. They can be used in various biomedical applications due to their novel physicochemical properties. In particular, the small size of CNTs, with a large surface area per unit volume, has a considerable impact on their toxicity. Despite of the use of CNTs in various applications, toxicity is a big problem that requires more research. In this Review, we discuss the toxicity of CNTs and the associated mechanisms. Physicochemical factors, such as metal impurities, length, size, solubilizing agents, CNTs functionalization, and agglomeration, that may lead to oxidative stress, toxic signaling pathways, and potential ways to control these mechanisms are also discussed. Moreover, with the latest mechanistic evidence described in this Review, we expect to give new insights into CNTs' toxicological effects at the molecular level and provide new clues for the mitigation of harmful effects emerging from exposure to CNTs.