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The electronic cigarettes (e-cigarettes, e-cigs) have become the most sought-after alternative to the traditional cigarettes, partly due to the widespread perception of safety. However, the high temperature reached by e-cig solutions can generate toxic compounds, some of which are listed as known human carcinogens. To evaluate the impact of e-cig aerosol on rat brain lipid profile, twenty male Sprague Dawley rats were exposed to 11 cycles/day (E-cig group), to consume 1 mL/day of e-liquid, for 5 days/week up to 8 weeks. Ten rats were sacrificed after 4 weeks (4w) and ten at the end of treatment (8w). The composition of total fatty acids, sterols and oxysterols of the lipid fraction of rat brains, was analyzed. The results of the E-cig group were compared with those of the control group (not exposed). After 8 weeks, the saturated fatty acids significantly raised up to 7.35 mg/g tissue, whereas polyunsaturated fatty acids decreased reaching 3.17 mg/g. The e-cig vaping increased both palmitic (3.43 mg/g) and stearic acids (3.82 mg/g), while a significant decrement of arachidonic (1.32 mg/g) and docosahexaenoic acids (1.00 mg/g) was found. Atherogenic (0.5) and thrombogenic (1.12) indices also increased in 8w treated animals. The e-cig aerosol significantly impacted the cholesterol homeostasis, since the latter at 8w (21.57 mg/g) was significantly lower than control (24.56 mg/g); moreover, a significant increase of 7-dehydrocholesterol (1.87 mg/g) was also denoted in e-cig group. The e-cig aerosol also reduced the oxysterol formation (19.55 μg/g) after 4 weeks of exposure, except for triol and 5α,6α-epoxycholesterol (α-EC). The principal component analysis (PCA) separated all E-cig from control groups, evidencing that oxysterols (except triol and 24(S)-hydroxycholesterol (24(S)-HC)) were inversely correlated to 7-DHC and TI. The present research revealed that e-cigs aerosol affected the lipid and cholesterol homeostasis in rat brain, which could contribute to the new occurrence of some neurodegenerative diseases.

Sulforaphane (SFN) and moringin (GMG-ITC) are edible isothiocyanates present as glucosinolate precursors in cruciferous vegetables and in the plant Moringa oleifera respectively, and recognized for their chemopreventive and medicinal properties. In contrast to the well-studied SFN, little is known about the molecular pathways targeted by GMG-ITC. We investigated the ability of GMG-ITC to inhibit essential signaling pathways that are frequently upregulated in cancer and immune disorders, such as JAK/STAT and NF-kappa B. We report for the first time that, similarly to SFN, GMG-ITC in the nanomolar range suppresses IL-3-induced expression of STAT5 target genes. GMG-ITC, like SFN, does not inhibit STAT5 phosphorylation, suggesting a downstream inhibitory event. Interestingly, treatment with GMG-ITC or SFN had a limited inhibitory effect on IFN alpha-induced STAT1 and STAT2 activity, indicating that both isothiocyanates differentially target JAK/STAT signaling pathways. Furthermore, we showed that GMG-ITC in the micromolar range is a more potent inhibitor of TNF-induced NF-kappa B activity than SFN. Finally, using a cellular system mimicking constitutive active STAT5-induced cell transformation, we demonstrated that SFN can reverse the survival and growth advantage mediated by oncogenic STAT5 and triggers cell death, therefore providing experimental evidence of a cancer chemopreventive activity of SFN. This work thus identified STAT5, and to a lesser extent STAT1/STAT2, as novel targets of moringin. It also contributes to a better understanding of the biological activities of the dietary isothiocyanates GMG-ITC and SFN and further supports their apparent beneficial role in the prevention of chronic illnesses such as cancer, inflammatory diseases and immune disorders.

Electronic cigarettes (e-cigs) are devices designed to deliver nicotine in a vaping solution rather than smoke and without tobacco combustion. Perceived as a safer alternative to conventional cigarettes, e-cigs are aggressively marketed as lifestyle-choice consumables, thanks to few restrictions and a lack of regulatory guidelines. E-cigs have also gained popularity among never-smokers and teenagers, becoming an emergent public health issue. Despite the burgeoning worldwide consumption of e-cigs, their safety remains largely unproven and it is unknown whether these devices cause in vivo toxicological effects that could contribute to cancer. Here we demonstrate the co-mutagenic and cancer-initiating effects of e-cig vapour in a rat lung model. We found that e-cigs have a powerful booster effect on phase-I carcinogen-bioactivating enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), and increase oxygen free radical production and DNA oxidation to 8-hydroxy-2'-deoxyguanosine. Furthermore, we found that e-cigs damage DNA not only at chromosomal level in peripheral blood, such as strand breaks in leucocytes and micronuclei formation in reticulocytes, but also at gene level such as point mutations in urine. Our results demonstrate that exposure to e-cigs could endanger human health, particularly among younger more vulnerable consumers.

Introduction: Obesity is recognized as a leading global health concern, associated with an increased risk for several chronic diseases. The brain plays a key role in energy homeostasis as the master regulator of food intake balance and energy expenditure, controlling the adipose mass gain responding to hormonal and nutrient-related signals. Promising weigh-management strategies include the use of vegetables rich in bioactive compounds, to improve the antioxidant status and to stimulate lipid catabolism. The aim of this study was to evaluate the dietary effects of Raphanus sativus cv Sango on lipid accumulation and oxysterols in brain of obese rats. Materials and Methods: Four-day old Raphanus sativus cv Sango sprouts (SSJ) were squeezed to obtain a juice, which was collected and used for the experiments. Thirty-five male Sprague Dawley rats aged 9 weeks (270–300 g), after 10-days adaptation, were split randomly into five groups (7 animals per group) and fed specific diets: RD-RD (regular diet for 14 weeks); HFD-HFD (high fat diet for 14 weeks); HFD-RD (HFD for 10 weeks and then RD for 4 weeks); HFD-RD 75 (HFD for 10 weeks and then RD and 75 mg/kg b.w. SSJ for 4 weeks); HFD-HFD 75 (HFD for 10 weeks and then HFD and 75 mg/kg b.w. SSJ for 4 weeks). After 14 weeks, rats’ brains were isolated and their lipid matter was subjected to the analysis of total fatty acids, sterols and oxysterols composition. Results: The lipid content, fatty acid composition, cholesterol and its oxidation products (COPs) content were significantly affected. The HFD-HFD group showed a fat accumulation in the brain, with a significant reduction of linoleic acid. Although the lowest cholesterol content was detected on HFD-HFD group, the latter generated the highest COPs amount (63.098 microg/g brain). The main COPs foundwere 7alfa/beta-hydroxycholesterol, alfa/beta-epoxycholesterols, 7-ketocholesterol, cholestanetriol and 24-hydroxycholesterol. The Principal Component Analysis revealed that all COPs were highly correlated to HFD-HFD diet, except for 24-hydroxycholesterol which resulted highly correlated to linoleic acid content. Conclusions: The high fat diet increased lipid infiltration in rat brain, however, it reduced the amount of cholesterol with a significant increase of COPs, except for 24-hydroxycholesterol, thus confirming the inflammatory status. However, the Raphanus sativus cv Sango sprouts supplementation was not able to counteract the oxidative stress in rat brain since the lipidomic profile was not significantly affected.

Objectives We used acetylsalicylic acid (ASA) as a probing agent to quantify hydroxyl radical (·OH) in Controls and patients with coronary artery disease and to prospectively investigate ·OH production in patients with myocardial infarction (MI) complicated by heart failure (HF). Background Oxidative stress status (OSS) is a mechanism for transition to HF in experimental heart injury models, but evidence for its causal role in humans is still limited. Methods Thirty healthy subjects (Controls), 12 patients with stable angina (Group 1), and 74 patients with ST-segment elevation MI (Group 2) were enrolled. A dose of 250 mg Flectadol was given intravenously before each blood collection to determine the 2,3-dihydroxybenzoic acid/salicylic acid (DHBA/SA) ratio. We also quantified vitamin E and coenzyme Q10to monitor antioxidant reserve, as well as tumor necrosis factor (TNF)-alpha, TNF-soluble receptors, interleukin (IL)-6, and IL-1ra to assess inflammatory status. All measurements were repeated at month 6 in Group 2. Results There were no differences between Controls and Group 1. Group 2 showed increased ·OH production, peaking at 24 h, whereas vitamin E and coenzyme Q10progressively declined. Group 2 patients developing HF during hospitalization (Group 2Bi) presented with an increase of both ·OH production at discharge and inflammatory status, as compared with patients without HF (Group 2Ai), persisting at month 6 in post-MI patients with HF (Group 2Bii). Conclusions We found a distinct pattern of ·OH generation in post-MI patients who show progression to HF. The interplay between OSS and inflammatory status should be targeted as a possible mechanism of progression to post-MI left ventricular dysfunction.

MONITORING OF DRINKING WATER QUALITY AT FERRARA CITY: STUDY OF METABOLIC PERTURBATION IN CYPRINUS CARPIO: Fabio Vivarelli, Donatella Canistro, Andrea Sapone, Moreno Paolini. In the global pollution scenario, a latent, and therefore insidious danger is the presence of toxic chemicals in drinking water, derived, paradoxically, from the disinfection process which is compulsory to protect public health from diseases. In most countries, the surface water is disinfected by chloro-derivatives which react with the dissolved organic matter (humic and fulvic acids), giving rise to the formation of carcinogenic organo-chlorinated by-products. Many of them, however, such as dichloroacetic acid and chloroform are not mutagens and act through epigenetic mechanisms. It is not to be underestimated the risk of gastrointestinal and urogenital tumors related to chronic exposure to these compounds, emerged from epidemiological investigations. This study is aimed to evaluate the possible effects on xenobiotic metabolism of fish (Cyprinus carpio) exposed to Ferrara city drinking water. It is known that the up-regulation of cytochrome P450 (CYP450) superfamily is associated with non-genotoxic (epigenetic) outcomes such as co-carcinogenesis (increasing bioactivation) and promotion (overgeneration of reactive free radicals). C. carpio, widely distributed in rivers and lakes, was recently considered an effective biomarker recommended by the EU to assess the toxic effects of chemicals in the aquatic environment. Animals were treated daily (3 or 6 consecutive days) intraperitoneally with concentrated drinking water collected from the distribution networks of the city, at 3L/eq dosage. The evaluation of metabolic perturbation has been performed in the hepatopancreas subcellular preparation. Four sampling points were selected: F-raw river water, A-water after treatment, R1 and R2-water from two points chosen along the network. After 3 day treatment, a marked and significant (p

Evidence from both epidemiological and experimental observations has fuelled the belief that the high consumption of fruits and vegetables rich in nutrients and phytochemicals may help prevent cancer and heart disease in humans. This concept has been drastically simplified from the dietary approaches to the use of single bioactive components both as a single supplement or in functional foods to manipulate xenobiotic metabolism. These procedures, which aim to induce mutagen/carcinogen detoxification or inhibit their bioactivation, fail to take into account the multiple and paradoxical biological outcomes of enzyme modulators that make their effects unpredictable. Here, we show that the idea that the physiological roles of specific catalysts may be easily manipulated by regular long-term administration of isolated nutrients and other chemicals derived from food plants is not viable. In contrast, we claim that the consumption of healthy diets is most likely to reduce mutagenesis and cancer risk, and that both research endeavours and dietary recommendations should be redirected away from single molecules to dietary patterns as a main strategy for public health policy.

The purpose of this study was to evaluate the efficacy of the radical scavenger IAC (bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) decantionate) in alleviating behavioral deficits and reducing amyloid-β (Aβ) accumulation in an Alzheimer's disease (AD) transgenic Tg2576 mouse model. Daily treatment with IAC (3-30 mg/kg, i.p.) was started at the age of 6 months and continued until the mice were 13 months old. At the age of 9 months and again at 12 months, the mice were tested in open field and water maze tests. At the age of 13 months, the mice were sacrificed and the brains processed for immunohistochemistry. Mortality was significantly reduced in all IAC-treated groups. In addition, IAC treatment improved the water maze hidden platform training performance but had no effect on motor activity in the open field or water maze swim speed in transgenic mice. Lastly, IAC treatment (10 mg/kg) significantly reduced the cortical Aβ plaque burden. In vitro, IAC is able to increase the number of neurites and neurite branches in cultured cortical primary neurons. In conclusion, IAC slowed down the development of the AD-like phenotype in Tg2576 mice and accelerated neurite growth in cultured neurons.

Lo stato di stress ossidativo (OSS) è stato di recente proposto come marker diagnostico per patologie cardiovascolari. È noto come l’OS sia un mancato bilanciamento tra generazione di radicali liberi (o di specie reattive all’ossigeno e all’azoto) e disponibilità di antiossidanti (di natura enzimatica e non) in un sistema biologico o compartimento. L’OSS può essere influenzato da molteplici fattori tra cui: dieta, esercizio fisico, esposizione ambientale/occupazionale e stile di vita quali tabagismo ed alcolismo. Sulla base dello studio di singole specie radicaliche, è stato osservato come un elevato OSS sia coinvolto nella genesi di placche aterosclerotiche, e disfunzioni endoteliali, creando un vero circolo vizioso. Nei nostri laboratori è stato di recente sviluppato un metodo per la determinazione dell’OSS direttamente su sangue periferico attraverso una metodica EPR basata sull’uso di una sonda radicalica (Radical-Probe-EPR). La sonda radicalica, bis(1-idrossi-2,2,6,6-tetrametil-4-piperidinil)decandioato di-cloridrato, reagisce istantaneamente e quantitativamente con i radicali centrati sull’ossigeno (inclusi il superossido e perossinitrito), generando un nitrossido sufficientemente stabile da poter essere misurato mediante spettroscopia EPR. Questa metodica minimizza le problematiche legate all’invasività, instabilità e specificità verso singole specie radicaliche riscontrate con i convenzionali “spin-trap”. Il Levosimendan, è un nuovo farmaco inotropo-vasodilatatore, usato nello shock cardiogeno che non aumenta il consumo di ossigeno, ha lunga durata d’azione (metaboliti attivi) e una migliore tolleranza rispetto ad altri farmaci somministrati in simili condizioni cliniche (dobutamina). La terapia è iniziata in unità coronarica sotto monitoraggio medico e laboratoristico; nell’arco temporale di un anno solare nella nostra unità coronarica sono stati trattati 15 pazienti con questo farmaco. In questo studio sono stati reclutati 5 pazienti (4 maschi ed 1 femmina), che, per la loro criticità clinica, necessitavano di trattamento. Il Levosimendan è stato somministrato in bolo alla dose di 12 microgrammi/Kg/10 minuti e successivamente, in infusione per 24 ore, 0.1 microgrammi/Kg/minuto. Dopo 1, 6 e 24 ore sono stati effettuati prelievi di sangue venoso immediatamente esposti con la sonda per la successiva indagine EPR durante monitoraggio emodinamico con linea arteriosa e catetere di Swan-Ganz in arteria polmonare. Il miglioramento riscontrato in questi pazienti in termini di riduzione dell’OSS andava da 30% ad un 55% alla ventiquattresima ora, e parallelo miglioramento dell’emodinamica. Il guadagno, in termini di ripresa di funzionalità ventricolare sinistra e condizioni cliniche generali, era già visibile alla sesta ora, anche se maggiore alla ventiquattresima ora. Questi risultati preliminari suggeriscono come il Levosimendan migliori la prognosi clinica dei pazienti sottoposti a trattamento anche attraverso una riduzione dello stress ossidativo.

Studi epidemiologici suggeriscono che una dieta ricca di frutta e verdura, per la presenza di innumerevoli molecole naturali (phytochemicals), sia in grado di prevenire danni di tipo ossidativo quali tumori, disfunzioni cardio-circolatorie, reumatismi e malattie neurodegenerative. I phytochemicals avrebbero pertanto un ruolo fondamentale nel ridurre il rischio di cancro, soprattutto per azione a livello dei meccanismi di difesa primaria della cellula. Una delle strategie chemiopreventive più evocata prevede un incremento della clearance di carcinogeni chimici ubiquitari, mediante induzione selettiva degli enzimi detossificanti (fase II del metabolismo) e/o inibizione di quelli bioattivanti (fase I), principalmente a livello epatico, da parte di specifici xenobiotici. Tra le sostanze più studiate in questo contesto vi sono sicuramente i composti fenolici. Al fine di studiare l’attività chemiopreventiva complessiva della pesca (cultivar Stark Red Gold), in relazione al contenuto in composti fenolici, ratti maschi del ceppo Sprague Dawley sono stati trattati per os, sia con liofilizzato di pesca in toto (250 e 500 mg/kg p.c., 2 volte/die per 7 e 14 gg consecutivi), sia con estratto di pesca (2.5 e 5 ml/kg p.c., 2 volte/die per 7 e 14 gg). La caratterizzazione qualitativa e quantitativa del profilo fenolico dell’estratto di pesca è stata ottenuta mediante analisi HPLC in fase inversa, ed ha riguardato entrambe i tessuti eduli (epicarpo e mesocarpo) di frutti giunti alla maturazione di consumo. L’indagine analitica sul profilo fenolico dei frutti considerati segnala la presenza di circa 10 composti principali appartenenti alle classi degli acidi cinnamici, flavanoli, flavonoli e cianidine. Le concentrazioni medie del complesso dei composti fenolici estratti si attestano su valori di 3 mg/g p.s. nella polpa e 7 mg/g p.s. nella buccia. Su frazioni microsomiali epatiche è stata studiata la modulazione del sistema monoossigenasico citocromo P450 dipendente (CYP) e di enzimi di fase II. I risultati ottenuti in seguito a trattamento sia con pesche in toto sia con estratto indicano un marcato effetto inattivante su diverse isoforme CYP. Per la componente post-ossidativa, i risultati mostrano un modesto effetto induttivo a carico della UDP-glucuronosil transferasi; al contrario, per la glutatione S-transferasi è stato registrato un significativo calo. Tali risultati, oltre a fornire una caratterizzazione metabolica (fingerprint) indotta dalla pesca e dall’estratto fenolico, totalmente assenti nella letteratura scientifica, forniscono indicazioni circa il meccanismo dell’attività protettiva di questo frutto. I risultati comparabili ottenuti tra le due matrici suggeriscono il predominante ruolo dei phytochemicals di natura fenolica nel determinare l’effetto biologico complessivo del frutto.

Hydrogen-potassium adenosine triphosphatase (H+/K+-ATPase)-target of omeprazole family members- present in gastric parietal cells, plays an essential role in the formation of HCl. It belongs to a family of P-type cation-transporting ATPases also including Ca2+-ATPase and Na+/K+ -ATPase. A 54 years old woman with a mildly degree hypertension (not pharmacologically treated), familiarity for CAD (father deceased after an AMI at the age of 60) and Helicobacter pylori positive gastritis, previously treated with antibiotics and antacid drugs, had being suffering for about two weeks for a gastric pyrosis recurrence. She started oral therapy with omeprazole 20 mg/die, but, still symptomatic, she was treated i.v. with ranitidine and spasmolytics. However, 8 days later, aspecific thoracic pain sensitive to deep inspiration, movements and digital pressure occurred. The ECG didn’t show any sign of acute ischemia and necrosis enzymes were normal. Furthermore, she was treated i.v. with 30 mg ketorolac, and 30 minutes later with 40 mg omeprazole. After few minutes, the patient had ventricular fibrillation, interrupted with a single 200 J DC-shock, and treated with magnesium sulphate in repolarizing solution i.v. The patient maintained always stable sinus rhythm: no further arrhythmias were recorded during her hospitalization and she kept asymptomatic. There were no signs of ischemia at ECG; all ematochemical parameters (CK, CK-MB, LDH, myoglobin and TnI), serum electrolytes, D-dimer and protein C reactive were always normal. In addition to routine laboratory tests, a peripheral blood sample for genetic analysis was taken with patient informed consent. To assess if clinical drugs-related side effects could be ascribe to genetic CYP-dependent drug metabolizing polymorphisms, DNA sample was analyzed. PCR-RFLP and sequencing of mutated CYP2C19 (variants: *2 and *3) and 3A4 (*1B, *2 and *3) alleles isoforms were performed. The homozygous mutations of both CYP isoforms recorded can be responsible of the abnormal omeprazole level and the consequent toxicity. In other words, high plasmatic level of this drug, not adequately metabolized, could target other receptors structurally similar the ones present in the stomach. So due the individual metabolic fingerprint when more than one principal metabolic pathway is “disrupted” serious side effects could be expected.

Epidemiological and animal studies linking high and varied fruit and vegetable intake to lower cancer risk, suggest the theoretical possibility that regular, long-term mass administration of isolated naturally occurring dietary constituents can provide a means of controlling cancer incidence. Although no exact mechanism of molecular chemoprotection is known, it is believed that the up-regulation of phase-II metabolizing enzymes by phytoalexins, such as sulforaphane - released from its thioglucoside natural precursor, glucoraphanin, by myrosinase hydrolysis – an isothiocyanate found in Cruciferae, could provide a defence against carcinogens.With the aim to verify such hypothesis, the effects of glucoraphanin supplementation on xenobiotic metabolizing enzymes were thus investigated in male and female Sprague-Dawley rats (aged 6-7 weeks, 150±15 g) receiving per os daily either 24 or 48 mg/kg b.w. glucoraphanin and, for comparison, either 120 or 240 mg/kg b.w. of the palmizio cauliflower extract (PCE – OD74 containing the same amount of glucoraphanin) for four consecutive days; controls received saline only and liver microsomes tested for various CYPs.Glucoraphanin slightly affected phase-II “detoxifying” enzymes, but powerfully induced phase-I bioactivating enzymes (P

The main purpose of this study was to compare the benefits of SSJ supplementation in obese rats with those achieved only by switching the alimentary regimen from high-fat (HFD) to the regular one (RD) in liver, ileum and prostate. Furthermore, changings in caecal chime microbiota were investigated. SSJ was administered to rats in combination with a RD (HFD-RD + SSJ). The switch from HFD to RD led to a weight loss of almost 9.8 g, and the total cholesterol was found to be significantly lower. In the HFD-RD + SSJ group, all values were improved compared with the HFD control, and the weight decrement was higher (-23.29 g) with respect to HFD-RD. HFD led to a widespread increment of oxidative stress (OS) markers in liver, ileum and prostate. SSJ has shown to improve the results achieved by the suspension of HFD and it has proven effective wherever the only switch in diet regimen failed.

Geraniol is a natural monoterpene showing anti-inflammatory, antioxidant, neuroprotective and anticancer effects. No pharmacokinetic and bioavailability data on geraniol are currently available. We therefore performed a systematic study to identify the permeation properties of geraniol across intestinal cells, and its pharmacokinetics and bioavailability after intravenous and oral administration to rats. In addition, we systematically investigated the potential hepatotoxic effects of high doses of geraniol on hepatic phase I, phase II and antioxidant enzymatic activities and undertook a hematochemical analysis on mice. Permeation studies performed via HPLC evidenced geraniol permeability coefficients across an in vitro model of the human intestinal wall for apical to basolateral and basolateral to apical transport of 13.10 ± 2.3 x 10−3 and 2.1 ± 0.1 x 10−3 cm/min, respectively. After intravenous administration of geraniol to rats (50 mg/kg), its concentration in whole blood (detected via HPLC) decreased following an apparent pseudo-first order kinetics with a half-life of 12.5 ± 1.5 minutes. The absolute bioavailability values of oral formulations (50 mg/kg) of emulsified geraniol or fiber-adsorbed geraniol were 92% and 16%, respectively. Following emulsified oral administration, geraniol amounts in the cerebrospinal fluid of rats ranged between 0.72 ± 0.08 µg/mL and 2.6 ± 0.2 µg/mL within 60 minutes. Mice treated with 120 mg/kg of geraniol for four weeks showed increased anti-oxidative defenses with no signs of liver toxicity. CYP450 enzyme activities appeared only slightly affected by the high dosage of geraniol.

Electronic cigarettes (e-cigs) are devices designed to deliver nicotine in a vaping solution rather than smoke and without tobacco combustion. Perceived as a safer alternative to conventional cigarettes, e-cigs are aggressively marketed as lifestyle-choice consumables, thanks to few restrictions and a lack of regulatory guidelines. E-cigs have also gained popularity among never-smokers and teenagers, becoming an emergent public health issue. Despite the burgeoning worldwide consumption of e-cigs, their safety remains largely unproven and it is unknown whether these devices cause in vivo toxicological effects that could contribute to cancer. Here we demonstrate the co-mutagenic and cancer-initiating effects of e-cig vapour in a rat lung model. We found that e-cigs have a powerful booster effect on phase-I carcinogen-bioactivating enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), and increase oxygen free radical production and DNA oxidation to 8-hydroxy-2′-deoxyguanosine. Furthermore, we found that e-cigs damage DNA not only at chromosomal level in peripheral blood, such as strand breaks in leucocytes and micronuclei formation in reticulocytes, but also at gene level such as point mutations in urine. Our results demonstrate that exposure to e-cigs could endanger human health, particularly among younger more vulnerable consumers.

The bis (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC), is an innovative non- radical scavenger used with success in numerous disease models such as inflammation, neurological disorders, hepatitis and diabetes. The pharmacological treatments have been performed by the intraperitoneal route of administration, representing to date, the main limit for the drug use. The aim of this study was to develop a delivery system that allows the oral administration of IAC while maintaining its therapeutic efficacy. Solid Lipid Microparticles (SLMs) containing a theoretical 18% (w/w) of IAC have been produced by the spray congealing technology; three formulations have been tested (A, B and C) using different low melting point carriers (stearic acid, Compritol® HD5ATO and carnauba wax) alone or in combination. All IAC loaded SLMs exhibited a spherical shape, encapsulation efficiency higher than 94% and particle size suitable for the oral route. Administered per os at different dosages in an inflammation rat model, all SLMs demonstrated their efficacy in reducing oedema and alleviating pain, compared to the gold standards Indomethacin and Paracetamol. These results suggested that the SLMs are an efficacious delivery system for the oral administration of IAC, potentially useful for the treatment of others diseases related to an over production of free radicals.

Over the past years, there has been a growing interest in the natural constituents of foods as a potential means of cancer control. To date, epidemiology studies seem to indicate an inverse association between regular consumption of fruit and vegetables and cancer risk. Here, the potential chemopreventive activity of the polyphenolic extract (PPE) of peach (Prunus persica L. Batsch) and of the freeze-dried fruit in toto (LFT), focusing on the modulation of xenobiotic metabolizing enzymes (XMEs) in vivo, was investigated. Rats were daily supplemented with LFT at 250 and 500 mg/kg b.w. or with the corresponding amount of PPE (2.5 and 5 mL/kg b.w., respectively) for either 7 or 14 days. While PPE treatment resulted in a widespread phase-I inactivation, a complex modulation pattern with drastic decreases (7α-testosterone hydroxylase, pentoxyresorufin O-dealkylase (PROD)), coupled with marked up-regulations of ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase (MROD) after LFT administration, was seen. A notable down-regulation (over 50%) following LFT or PPE treatment for the phase-II enzymes was also recorded. The observed remarkable changes in XMEs, if reproduced in humans, might have public health implications. These data suggest caution in promoting peach fruit (mono-diet) consumption or its polyphenolic extract in the field of chemoprevention.

Fruit and vegetables (FV) have long been considered a panacea against major chronic diseases, including cancer. However, there is no convincing epidemiological, clinical or experimental evidence supporting FV chemopreventive ability. A daily mono-supplementation of lyophilized onion, tomato, peach, black grape or lettuce was compared with the daily combined administration of the same FV (5 a day-like diet). Ten days post-treatment, the phase-I/II xenobiotic metabolizing and antioxidant enzyme activities, protein and mRNA levels were investigated. As a marker of oxidative stress, the level of hydroperoxides was measured in rat serum samples. Here we show that a blend of FV orally administered to rats not only potentially manipulates metabolism but also disrupts systemic oxidative homeostasis. A daily combination of the five servings remarkably down-regulates the catalytic activity, protein and mRNA levels of a cohort of hepatic metabolizing enzymes, suggesting a possible depressed clearance upon exposure to ubiquitous carcinogens. Strikingly, we observed an impairment of antioxidant enzymes with a boost in systemic hydroperoxide levels. Our study identifies new potential factors of cancer risk connected with the persistent consumption of fixed servings of FV, suggesting that dietary guidance should rely on a "daily diversification" of FV.

Drinking water (DW) disinfection represents a milestone of the past century, thanks to its efficacy in the reduction of risks of epidemic forms by water micro-organisms. Nevertheless, such process generates disinfection by-products (DBPs), some of which are genotoxic both in animals and in humans and carcinogenic in animals. At present, chlorination is one of the most employed strategies but the toxicological effects of several classes of DBPs are unknown. In this investigation, a multidisciplinary approach foreseeing the chemical analysis of chlorinated DW samples and the study of its effects on mixed function oxidases (MFOs) belonging to the superfamily of cytochrome P450-linked monooxygenases of Cyprinus carpio hepatopancreas, was employed. The experimental samples derived from aquifers of two Italian towns (plant 1, river water and plant 2, spring water) were obtained immediately after the disinfection (A) and along the network (R1). Animals treated with plant 1 DW-processed fractions showed a general CYP-associated MFO induction. By contrast, in plant 2, a complex modulation pattern was achieved, with a general up-regulation for the point A and a marked MFO inactivation in the R1 group, particularly for the testosterone metabolism. Together, the toxicity and co-carcinogenicity (i.e. unremitting over-generation of free radicals and increased bioactivation capability) of DW linked to the recorded metabolic manipulation, suggests that a prolonged exposure to chlorine-derived disinfectants may produce adverse health effects.