Aristidis M. Tsatsakis

Histopathological lesions, oxidative stress and genotoxic effects in liver and kidneys following long term exposure of rabbits to diazinon and propoxur.

PURPOSE The aim of the present study was to investigate the effects of diazinon and propoxur on liver and kidneys, following long term exposure of rabbits. METHODS Ten New Zealand white female rabbits were used. The animals were divided into 5 groups, consisting of 2 animals each. Diazinon (groups 1 and 2) and propoxur (groups 3 and 4) were administered at 2 different doses, and group 5 served as the control group. Histopathological lesions in the liver and kidneys, oxidative stress and oxidative DNA damage were evaluated. RESULTS Both pesticides induced focal inflammation and fibrosis in the liver and kidneys. The low dose of propoxur induced a significant increase in total antioxidant capacity (TAC), with no difference in reduced glutathione (GSH), while the high dose of propoxur induced an increase in GSH with no change in TAC. For diazinon-exposed animals, the opposite findings were observed. Both diazinon and propoxur induced a statistically significant oxidative DNA damage in the liver and kidneys and a subsequent increase in telomerase activity in these tissues, possibly as a counteracting mechanism. Furthermore, systemic inflammation, as depicted by the dose-dependent increase in telomerase activity in peripheral blood mononuclear cells (PBMCs), was observed in propoxur treated animals. CONCLUSIONS Histopathological lesions, oxidative stress and genotoxic effects were induced in liver and kidneys following long term exposure of rabbits to diazinon and propoxur.

Acute impact of active and passive electronic cigarette smoking on serum cotinine and lung function

Abstract Context: Electronic cigarettes (e-cigarettes) are becoming increasingly popular yet their effects on health remain unknown. Objective: To conduct the first comprehensive and standardized assessment of the acute impact of active and passive e-cigarette smoking on serum cotinine and lung function, as compared to active and passive tobacco cigarette smoking. Materials and methods: Fifteen smokers (≥15 cigarettes/day; seven females; eight males) and 15 never-smokers (seven females; eight males) completed this repeated-measures controlled study. Smokers underwent a control session, an active tobacco cigarette (their favorite brand) smoking session and an active e-cigarette smoking session. Never-smokers underwent a control session, a passive tobacco cigarette smoking session and a passive e-cigarette smoking session. Serum cotinine, lung function, exhaled carbon monoxide and nitric oxide were assessed. The level of significance was set at p ≤ 0.001 to adjust for multiple comparisons. Results: e-Cigarettes and tobacco cigarettes generated similar (p > 0.001) effects on serum cotinine levels after active (60.6 ± 34.3 versus 61.3 ± 36.6 ng/ml) and passive (2.4 ± 0.9 versus 2.6 ± 0.6 ng/ml) smoking. Neither a brief session of active e-cigarette smoking (indicative: 3% reduction in FEV1/FVC) nor a 1 h passive e-cigarette smoking (indicative: 2.3% reduction in FEV1/FVC) significantly affected the lung function (p > 0.001). In contrast, active (indicative: 7.2% reduction in FEV1/FVC; p < 0.001) but not passive (indicative: 3.4% reduction in FEV1/FVC; p = 0.005) tobacco cigarette smoking undermined lung function. Conclusion: Regarding short-term usage, the studied e-cigarettes generate smaller changes in lung function but similar nicotinergic impact to tobacco cigarettes. Future research should target the health effects of long-term e-cigarette usage, including the effects of nicotine dosage.

Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism.

Toxic effects of pesticide mixtures at a molecular level: their relevance to human health.

Pesticides almost always occur in mixtures with other ones. The toxicological effects of low-dose pesticide mixtures on the human health are largely unknown, although there are growing concerns about their safety. The combined toxicological effects of two or more components of a pesticide mixture can take one of three forms: independent, dose addition or interaction. Not all mixtures of pesticides with similar chemical structures produce additive effects; thus, if they act on multiple sites their mixtures may produce different toxic effects. The additive approach also fails when evaluating mixtures that involve a secondary chemical that changes the toxicokinetics of the pesticide as a result of its increased activation or decreased detoxification, which is followed by an enhanced or reduced toxicity, respectively. This review addresses a number of toxicological interactions of pesticide mixtures at a molecular level. Examples of such interactions include the postulated mechanisms for the potentiation of pyrethroid, carbaryl and triazine herbicides toxicity by organophosphates; how the toxicity of some organophosphates can be potentiated by other organophosphates or by previous exposure to organochlorines; the synergism between pyrethroid and carbamate compounds and the antagonism between triazine herbicides and prochloraz. Particular interactions are also addressed, such as those of pesticides acting as endocrine disruptors, the cumulative toxicity of organophosphates and organochlorines resulting in estrogenic effects and the promotion of organophosphate-induced delayed polyneuropathy.

Persistent organochlorinated pesticides and mechanisms of their toxicity.

Persistent organic pollutants comprised of organic chemicals like polychlorinated biphenyls, dibenzo-p-dioxins, dibenzofurans and organochlorinated pesticides which have many characteristics in common. Once released in the environment they resist physical, biological, chemical and photochemical breakdown processes and thus persist in the environment. They are subject to long transboundary air pollution transport. They accumulate in the food chain due to their lipophilicity, bioaccumulation and biomagnification properties. Human exposure occurs through inhalation of air, ingestion of food and skin contact. Because most of them bioaccumulate and remain preferentially in fat, their long-term effects are still a matter of public health concern. They are condemned for health adverse effects such as cancer, reproductive defects, neurobehavioral abnormalities, endocrine and immunological toxicity. These effects can be elicited via a number of mechanisms among others include disruption of endocrine system, oxidation stress and epigenetic. However most of the mechanisms are not clear thus a number of studies are ongoing trying to elucidate them. In this review, the underlying possible mechanisms of action and their possible roles in adverse developmental and reproductive processes are discussed and where possible a linkage is made to some existing epidemiological data. Both genomic and nongenomic pathways are used to describe these effects. Understanding of these mechanisms will enable development of strategies to protect the public by reducing these adverse effects. This review is limited to persistent organochlorinated pesticides (OCPs) such as dichlorodiphenyltrichloroethane (DDT) and its metabolites, hexachlorobenzene (HCB), beta-hexachlorocyclohexane (β-HCH) and endosulfan.

Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases—A mechanistic approach

The etiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. The role of pesticide exposure in neurodegenerative disease has long been suspected, but the specific causative agents and the mechanisms underlying are not fully understood. For the main neurodegenerative diseases such as Parkinsons disease, Alzheimers disease and amyotrophic lateral sclerosis there are evidences linking their etiology with long-term/low-dose exposure to pesticides such as paraquat, maneb, dieldrin, pyrethroids and organophosphates. Most of these pesticides share common features, namely the ability to induce oxidative stress, mitochondrial dysfunction, α-synuclein fibrillization and neuronal cell loss. This review aims to clarify the role of pesticides as environmental risk factors in genesis of idiopathic PD and other neurological syndromes. For this purpose, the most relevant epidemiological and experimental data is highlighted in order to discuss the molecular mechanisms involved in neurodegeneration.

Dietary flavonoids in cancer therapy and prevention: Substrates and inhibitors of cytochrome P450 CYP1 enzymes

Flavonoids are polyphenolic compounds that have attracted the attention of the scientific community as the hallmark molecules responsible for cancer prevention by a plethora of different mechanisms. One of their most important characteristics, responsible for their cancer preventive properties, is their interaction with cytochrome P450 CYP1 enzymes. Flavonoids have traditionally been described as CYP1 inhibitors due to the inhibition of carcinogenic product formation and consequent blockage of the initiation stage of carcinogenesis. However, mounting evidence indicate that flavonoids are also capable of acting as CYP1 substrates, undergoing bioactivation to more antiproliferative agents within cancer cells. In this review, a comprehensive summary of the two models is presented. Structural features responsible for CYP1 inhibition or substrate turnover are discussed and limitations as well as discrepancies between procarcinogen-activating and 7-ethoxyresorufin-inhibition assay systems are further explored in vitro and in vivo. Moreover, a thorough investigation of the substrate specificity of flavonoids for the active site of CYP1 enzymes is undertaken. Finally, issues concerning the bioavailability and metabolic fate of these compounds in vivo are addressed. Ultimately, the mode of flavonoid action, in terms of CYP1 inhibition or CYP1-mediated bioactivation, is dependent on the lipophilicity or hydrophilicity of each compound. The degree of hydroxylation or methoxylation of the A and B rings is the major factor which determines the accessibility to the tumor site, in terms of hepatic and intestinal metabolism, and the introduction of the molecules to the CYP1 active site, respectively.

Acute effects of electronic and tobacco cigarette smoking on complete blood count

The World Health Organisation called for research assessing the safety of electronic cigarette (e-cigarette). We evaluated the acute effect of active and passive e-cigarette and tobacco cigarette smoking on complete blood count (CBC) markers in 15 smokers and 15 never-smokers, respectively. Smokers underwent a control session, an active tobacco cigarette smoking session, and an active e-cigarette smoking session. Never-smokers underwent a control session, a passive tobacco cigarette smoking session, and a passive e-cigarette smoking session. The results demonstrated that CBC indices remained unchanged during the control session and the active and passive e-cigarette smoking sessions (P>0.05). Active and passive tobacco cigarette smoking increased white blood cell, lymphocyte, and granulocyte counts for at least one hour in smokers and never smokers (P<0.05). It is concluded that acute active and passive smoking using the e-cigarettes tested in the current study does not influence CBC indices in smokers and never smokers, respectively. In contrast, acute active and passive tobacco cigarette smoking increase the secondary proteins of acute inflammatory load for at least one hour. More research is needed to evaluate chemical safety issues and other areas of consumer product safety of e-cigarettes, because the nicotine content in the liquids used may vary considerably.

Acute and Short-term Effects of Secondhand Smoke on Lung Function and Cytokine Production

RATIONALE The acute effect of secondhand smoke (SHS) on lung function and the duration of system disruption remain unknown. OBJECTIVES To assess the SHS effects and their duration on lung function and inflammatory markers. METHODS In a randomized single-blind crossover experiment data were obtained from 16 (8 women) nonsmoking adults at baseline and at 0, 1, and 3 hours after a 1-hour SHS exposure set at bar/restaurant SHS levels. MEASUREMENTS AND MAIN RESULTS Serum and urine cotinine, lung function, and cytokines IL-4, IL-5, IL-6, tumor necrosis factor (TNF)-alpha, and IFN-gamma. At 0 hours most lung function parameters were significantly reduced (indicative: FEV(1), 4.3 +/- 0.4 vs. 3.8 +/- 0.3 L; FEV(1)/FVC, 0.9 +/- 0.1 vs. 0.8 +/- 0.1; P < 0.05) but at 3 hours they were at baseline levels. In contrast, cotinine (serum, 8.9 +/- 3.2 vs. 35.5 +/- 10.2 ng x ml(-1)), IL-4 (41.3 +/- 5.8 vs. 44.2 +/- 4.5 pg x ml(-1)), IL-5 (36.1 +/- 3.2 vs. 60.1 +/- 7.0 pg x ml(-1)), IL-6 (2.5 +/- 0.3 vs. 7.6 +/- 1.4 pg x ml(-1)) and IFN-gamma (0.3 +/- 0.2 vs. 0.6 +/- 0.2 IU x ml(-1)) at 3 hours were higher than at baseline (P < 0.05). IL-4 and TNF-alpha increased only in men, whereas IL-5, IL-6, and IFN-gamma were different between sexes after exposure (P < 0.05). Regression analyses revealed inverse associations of FEV(1) and FEV(1)/FVC ratio with IL-5 (P < 0.05) in men and with IL-5 (P = 0.01), IL-6 (P < 0.001), IFN-gamma (P = 0.034) and serum cotinine (P < 0.001) in women. CONCLUSIONS We conclude that 1 hour of SHS exposure at bar/restaurant levels is accompanied by significant decrements on lung function and marked increases in inflammatory cytokines, particularly in men. More importantly, whereas most smoke-induced effects on lung function appear to recede within 60 minutes, inflammatory cytokines remain elevated for at least 3 hours after exposure to SHS.

Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)

Targeted cancer therapies are used to inhibit the growth, progression, and metastasis of the tumor by interfering with specific molecular targets and are currently the focus of anticancer drug development. Protein kinase B, also known as Akt, plays a central role in many types of cancer and has been validated as a therapeutic target nearly two decades ago. This review summarizes the intracellular functions of Akt as a pivotal point of converging signaling pathways involved in cell growth, proliferation, apoptotis and neo-angiogenesis, and focuses on the drug design strategies to develop potent anticancer agents targeting Akt. The discovery process of Akt inhibitors has evolved from adenosine triphosphate (ATP)-competitive agents to alternative approaches employing allosteric sites in order to overcome the high degree of structural similarity between Akt isoforms in the catalytic domain, and considerable structural analogy to the AGC kinase family. This process has led to the discovery of inhibitors with greater specificity, reduced side-effects and lower toxicity. A second generation of Akt has inhibitors emerged by incorporating a chemically reactive Michael acceptor template to target the nucleophile cysteines in the catalytic activation loop. The review outlines the development of several promising drug candidates emphasizing the importance of each chemical scaffold. We explore the pipeline of Akt inhibitors and their preclinical and clinical examination status, presenting the potential clinical application of these agents as a monotherapy or in combination with ionizing radiation, other targeted therapies, or chemotherapy.