Effects of Vitamin E on carcinogen metabolizing enzymes and redox homeostasis

Negli ultimi decenni, in virtù delle eccellenti proprietà antiossidanti della vitamina E (VE), la possibile associazione tra questa e la riduzione dell’incidenza di patologie neoplastiche è stata studiata mediante numerosi trial clinici. I risultati sono però ambigui e l’impiego della VE come agente chemiopreventivo su larga scala è oggi più che mai al centro del dibattito scientifico. Il Selenium and Vitamin E Cancer Prevention Trial (SELECT) ha addirittura evidenziato un rischio d’incidenza più alto per il cancro alla prostata nel gruppo d’intervento in cui è stata somministrata la VE. Tuttavia, il meccanismo d’azione non è noto. Poiché la VE induce l’espressione di alcune isoforme del P450 nel fegato e poichè tale induzione è associata ad un aumento della produzione di specie reattive centrate sull’ossigeno, ci siamo posti il problema di come un’eventuale up-regulation a livello prostatico avrebbe potuto generare uno stress ossidativo responsabile del fenomeno di cui sopra. Il presente lavoro ha mostrato come la VE provochi una marcata induzione delle isoforme CY1A1, CYP1A2, e CYP1B1/2 nel rene e nella prostata di ratto trattato i.p. con VE (100 o 200 mg/kg p.c. per sette o quattordici giorni consecutivi), e nel rene una generale inattivazione degli enzimi post-ossidativi GST e UDPGT ed una riduzione della potenzialità antiossidante. La spettroscopia EPR abbinata alla tecnica radical trapping ha rilevato una generazione anomala di radicali liberi in entrambi i tessuti. I risultati sono stati confermati in vitro in cellule epiteliali di prostata umana RWPE-1 esposte alla VE. Insieme ad un aumento dell’espressione genica (mRNA) di differenti CYPs, è stato osservato un incremento di radicali liberi e della prostaglandina E2 (PGE2) rispetto al controllo. Lo studio indica che la VE induce la superfamiglia CYP e uno stress ossidativo a livello prostatico (co-cancerogenesi) e può contribuire a spiegare i risultati inaspettati del trial SELECT.Several meta-analysis and randomized clinical trials have seriously questioned chemoprevention based on vitamins including vitamin E (VE). Recently, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) has pointed out an increased risk for prostate cancer among VE long–term users. However, to date, the mechanism underlying these findings still remain unknown. Evidence from both in vitro and in vivo models reported how VE might increase the expression of hepatic cytochrome P450 (CYP). Induction may increase the biotransformation of ubiquitous pre-carcinogens and trigger an over-production of oxygen centred radicals (ROS) in the target tissue. We apotheosized that if such phenomenon occured also in the prostate, it could contribute to explain the SELECT unexpected data. Male Sprague-Dawley rats were daily treated i.p. with either 100 or 200 mg/kg b.w. for 7 or 14 consecutive days. A powerful booster effect of various CYP isoforms such as CY1A1, CYP1A2, and CYP1B1/2, coupled with a marked free radical over-generation were recorded in renal and prostate tissues. VE treatment led to a wide down-regulation of antioxidant (catalase, NAD(P)H:quinone reductase) and phase II enzymes (glutathione S-transferase, UDP-glucuronosyl transferase capability. Results observed in the in vivo study were consistent with those obtained by the use of a RWPE-1 human prostate cell based model. Compared to the control RWPE-1, cells exposed to VE reported a general CYP up-regulation associated with a higher content of free radicals. Interestingly, VE treatment also induced the cyclooxygenase (COX-2) expression with a consequently increased of the prostaglandin E2 levels. The present study suggests that VE can act as a co-carcinogen and pro-oxidant agent. If such epigenetic mechanisms occur in human, may contribute to explain the harmful outcomes raised up from the SELECT study

Labour‐saving automation: A direct measure of occupational exposure

This article represents one of the first attempts at building a direct measure of occupational exposure to robotic labour-saving technologies. After identifying robotic and labour-saving robotic patents, the underlying 4-digit CPC (Cooperative Patent Classification) code definitions, together with O*NET (Occupational Information Network) task descriptions, are employed to detect functions and operations which are more directed to substituting the labour input and their exposure to labour-saving automation. This measure allows us to obtain fine-grained information on tasks and occupations according to their text similarity ranking. Occupational exposure by wage and employment dynamics in the United States is then studied, and complemented by investigating industry and geographical penetration rates

Moderate exercise improves cardiac hypertrophy in female aged mice

Age-related diastolic dysfunction has a significant impact on the elderly health, in fact the left ventricular filling is impaired, limiting intense exercise tolerance and reducing the quality of life. Pathological hypertrophy is commonly associated with up-regulation of fetal genes, fibrosis, cardiac dysfunction, fat deposits and increased mortality. Regular and moderate physical activity improves cardiac performance in elderly people. Type 5 cyclic nucleotide phosphodiesterase (PDE5) regulates intracellular cGMP levels and its increased expression has an important role in the development of cardiac hypertrophy (1). Our hypothesis is to assess if moderate exercise modulates PDE5 expression and reduces cardiac hypertrophy in old mice. CD1 female mice were grouped in young (2 months) sedentary (YS), young trained (YE), old 20 months sedentary (OS) and old old trained (OE). Exercise was performed at moderate intensity (speed of 13 m/min, for 30 minutes) on tapis roulant for 5 days/week. Morphometric (left ventricular weight/tibial length ratio) and histological (cardiomyocyte size) analyses showed that cardiac hypertrophy is present in OS compared to YS and YE and significantly reduced in OE group compared to OS. Moderate exercise also attenuated cardiac fibrosis in OE group. Molecular analysis revealed that hypertrophic markers such as ANP, BNP, GATA 4 and NKX 2.5 were significantly down-regulated in OE group. SIRT1 and PPARα, two regulators of oxidative stress and fat metabolism, were up-regulated in aged trained mice. PDE5 expression is down-regulated after exercise in OE group. These results suggest that exercise leads to a beneficial effect in old mice. Interestingly PDE5 expression correlates with the anti-hypertrophic effect of training in old mice

Toxicological Aspects Associated with Consumption from Electronic Nicotine Delivery System (ENDS): Focus on Heavy Metals Exposure and Cancer Risk

Tobacco smoking remains one of the leading causes of premature death worldwide. Electronic Nicotine Delivery Systems (ENDSs) are proposed as a tool for smoking cessation. In the last few years, a growing number of different types of ENDSs were launched onto the market. Despite the manufacturing differences, ENDSs can be classified as “liquid e-cigarettes” (e-cigs) equipped with an atomizer that vaporizes a liquid composed of vegetable glycerin (VG), polypropylene glycol (PG), and nicotine, with the possible addition of flavorings; otherwise, the “heated tobacco products” (HTPs) heat tobacco sticks through contact with an electronic heating metal element. The presence of some metals in the heating systems, as well as in solder joints, involves the possibility that heavy metal ions can move from these components to the liquid, or they can be adsorbed into the tobacco stick from the heating blade in the case of HTPs. Recent evidence has indicated the presence of heavy metals in the refill liquids and in the mainstream such as arsenic (As), cadmium (Cd), chromium (Cr), nickel (Ni), copper (Cu), and lead (Pb). The present review discusses the toxicological aspects associated with the exposition of heavy metals by consumption from ENDSs, focusing on metal carcinogenesis risk

Effects of unburned tobacco smoke on inflammatory and oxidative mediators in the rat prefrontal cortex

Although the Food and Drug Administration has authorized the marketing of "heat-not-burn" (HnB) electronic cigarettes as a modified risk tobacco product (MRTP), toxicological effects of HnB smoke exposure on the brain are still unexplored. Here, paramagnetic resonance of the prefrontal cortex (PFC) of HnB-exposed rats shows a dramatic increase in reactive radical species (RRS) yield coupled with an inflammatory response mediated by NF-κB-target genes including TNF-α, IL-1β, and IL-6 and the downregulation of peroxisome proliferator-activated receptor (PPAR) alpha and gamma expression. The PFC shows higher levels of 8-hydroxyguanosine, a marker of DNA oxidative damage, along with the activation of antioxidant machinery and DNA repair systems, including xeroderma pigmentosum group C (XPC) protein complex and 8-oxoguanine DNA glycosylase 1. HnB also induces the expression of drug-metabolizing enzymes such as CYP1A1, CYP2A6, CYP2B6, and CYP2E, particularly involved in the biotransformation of nicotine and several carcinogenic agents such as aldehydes and polycyclic aromatic hydrocarbons here recorded in the HnB stick smoke. Taken together, these effects, from disruption of redox homeostasis, inflammation, PPAR manipulation along with enhanced bioactivation of neurotoxicants, and upregulation of cMYC protooncogene to impairment of primary cellular defense mechanisms, suggest a possible increased risk of brain cancer. Although the HnB device reduces the emission of tobacco toxicants, our findings indicate that its consumption may carry a risk of potential adverse health effects, especially in non-smokers so far. Further studies are needed to fully understand the long-term effects of these devices

Potential Harm of IQOS Smoke to Rat Liver

The Food and Drug Administration has recently classified the IQOS electronic cigarette as a modified-risk tobacco product. However, IQOS cigarettes still release various harmful constituents typical of conventional cigarettes (CCs), although the concentrations are markedly lower. Here, we investigated the damaging effects of IQOS smoking on the liver. Male Sprague Dawley rats were exposed, whole body, 5 days/week for 4 weeks to IQOS smoke (4 sticks/day), and hepatic xenobiotic metabolism, redox homeostasis and lipidomic profile were investigated. IQOS boosted reactive radicals and generated oxidative stress. Exposure decreased cellular reserves of total glutathione (GSH) but not GSH-dependent antioxidant enzymes. Catalase and xanthine oxidase were greater in the exposed group, as were various hepatic CYP-dependent monooxygenases (CYP2B1/2, CYP1A1, CYP2A1, CYP2E1-linked). Respiratory chain activity was unaltered, while the number of liver mitochondria was increased. IQOS exposure had an impact on the hepatic lipid profile. With regard to the expression of some MAP kinases commonly activated by CC smoking, IQOS increased the p-p38/p38 ratio, while erythroid nuclear transcription factor 2 (Nrf2) was negatively affected. Our data suggest that IQOS significantly impairs liver function, supporting the precautionary stance taken by the WHO toward the use of these devices, especially by young people and pregnant women

On the toxicity of e-cigarettes consumption: Focus on pathological cellular mechanisms

Tobacco smoking remains without a doubt one of the leading causes of premature death worldwide. In combination with conventional protocols for smoking cessation, e-cigarettes have been proposed as a useful tool to quit smoking. Advertised as almost free of toxic effects, e-cigarettes have rapidly increased their popularity, becoming a sought-after device, especially among young people. Recently some health concerns about e-cigarette consumption are being raised. It is well known that they can release several toxic compounds, some of which are carcinogenic to humans, and emerging results are now outlining the risks related to the onset of respiratory and cardiovascular diseases and even cancer. The present review shows the emerging evidence about the role of technical components of the devices, the e-liquid composition as well as customization by consumers. The primary topics we discuss are the main toxicological aspects associated with e-cigarette consumption, focusing on the molecular pathways involved. Here it will be shown how exposure to e-cigarette aerosol induces stress/mitochondrial toxicity, DNA breaks/fragmentation following the same pathological pathways triggered by tobacco smoke, including the deregulation of molecular signalling axis associated with cancer progression and cell migration. Risk to fertility and pregnancy, as well as cardiovascular risk associated with e-cigarette use, have also been reported.This work was supported by a grant from the Italian Ministry of Education, University and Research. S.G., PhD fellowship grants were awarded from the Italian Ministry of Education, University and Research. L.R. and F.V. postdoctoral fellowship grant was cofounded by D.C., M.P., S.C., and P.R.; I.C-C. was supported by a postdoctoral fellowship from the Andalusian Government Ministry of Economy, Knowledge, Business, and University (DOC_00587/2020).Peer reviewe

Liver and intestinal protective effects of Castanea sativa Mill. bark extract in high-fat diet rats

The effects of Castanea sativa Mill. have been studied in high fat diet (HFD) overweight rats. Natural Extract of Chestnut bark (Castanea sativa Mill.) (ENC®), rich in ellagitannins, has been studied in 120 male Sprague-Dawley rats, divided in four groups. Two groups were controls: regular (RD) and HDF diet. Two groups received ENC®(20 mg/kg/day): RD + ENC®and HFD + ENC®. At baseline and at 7, 14 and 21 days, weight gain, serum lipids, plasma cytokines, liver histology, microsomial enzymes and oxidation, intestinal oxidative stress and contractility were studied. HFD increased body weight, increased pro-inflammatory cytokines, induced hepatocytes microvescicular steatosis, altered microsomial, increased liver and intestinal oxidative stress, deranged intestinal contractility. In HFD-fed rats, ENC®exerted antiadipose and antioxidative activities and normalized intestinal contractility, suggesting a potential approach to overweight management associated diseases

β1-Syntrophin Modulation by miR-222 in mdx Mice

Background: In mdx mice, the absence of dystrophin leads to the deficiency of other components of the dystrophin-glycoprotein complex (DAPC), making skeletal muscle fibers more susceptible to necrosis. The mechanisms involved in the disappearance of the DAPC are not completely understood. The muscles of mdx mice express normal amounts of mRNA for the DAPC components, thus suggesting post-transcriptional regulation. Methodology/Principal Findings: We investigated the hypothesis that DAPC reduction could be associated with the microRNA system. Among the possible microRNAs (miRs) found to be upregulated in the skeletal muscle tissue of mdx compared to wt mice, we demonstrated that miR-222 specifically binds to the 3′-UTR of β1-syntrophin and participates in the downregulation of β1-syntrophin. In addition, we documented an altered regulation of the 3′-UTR of β1-syntrophin in muscle tissue from dystrophic mice. Conclusion/Significance: These results show the importance of the microRNA system in the regulation of DAPC components in dystrophic muscle, and suggest a potential role of miRs in the pathophysiology of dystrophy. © 2010 De Arcangelis et al