DNA repair systems in malignant mesothelioma

Malignant mesothelioma (MM) is an aggressive tumor of serosal surfaces with increasing incidence and poor prognosis. Asbestos exposure is the main cause of MM and asbestos-induced DNA damage is critical for MM pathogenesis. The present review summarizes the implications of DNA repair systems in MM development, focusing on gene expression alterations and single nucleotide polymorphisms of genes encoding for DNA repair enzymes. The involvement of DNA repair systems in MM improves understanding of MM pathogenesis and provides novel therapeutical targets. © 2011 Elsevier Ireland Ltd

Toxicogenomics: A pivotal piece in the puzzle of toxicological research

Toxicogenomics, resulting from the merge of conventional toxicology with functional genomics, being the scientific field studying the complex interactions between the cellular genome, toxic agents in the environment, organ dysfunction and disease state. When an organism is exposed to a toxic agent the cells respond by altering the pattern of gene expression. Genes are transcribed into mRNA, which in turn is translated into proteins that serve in a variety of cellular functions. Toxicogenomics through microarray technology, offers large-scale detection and quantification of mRNA transcripts, related to alterations in mRNA stability or gene regulation. This may prove advantageous in toxicological research. In the present review, the applications of toxicogenomics, especially to mechanistic and predictive toxicology are reported. The limitations arising from the use of this technology are also discussed. Additionally, a brief report of other approaches, using other -omic technologies (proteomics and metabonomics) that overcome limitations and give global information related to toxicity, is included. Copyright © 2007 John Wiley & Sons, Ltd

Peroxisome proliferator activated receptor-gamma ligands as potent antineoplastic agents

The Peroxisome Proliferator Activated Receptors (PPARs) are initially described as molecular targets for compounds inducing peroxisome proliferation. Among the three PPAR subtypes (alpha, beta, gamma), PPAR-gamma acting as a ligand-activated transcription factor, proved to be an important regulator of adipogenic differentiation and glucose homeostasis. Recent data support evidence for participation of PPAR-gamma, upon ligands activation, in the biological mechanisms underlying the carcinogenic evolution. Specific PPAR-gamma ligands affect cancer cells proliferation and differentiation acting as cell cycle modulators, suggesting their use as an important tool for future therapeutic approach in cancer. In this review, the latest knowledge on PPAR-gamma activation and molecular mechanisms of PPAR-gamma ligands mediated anti-tumoral activity are presented. In vitro and in vivo studies concerning the use of PPAR-gamma ligands in different cancer types are also included

Doping and musculoskeletal system: Short-term and long-lasting effects of doping agents

Doping is a problem that has plagued the world of competition and sports for ages. Even before the dawn of Olympic history in ancient Greece, competitors have looked for artificial means to improve athletic performance. Since ancient times, athletes have attempted to gain an unfair competitive advantage through the use of doping substances. A Prohibited List of doping substances and methods banned in sports is published yearly by the World Anti-Doping Agency. Among the substances included are steroidal and peptide hormones and their modulators, stimulants, glucocorticosteroids, β 2-agonists, diuretics and masking agents, narcotics, and cannabinoids. Blood doping, tampering, infusions, and gene doping are examples of prohibited methods indicated on the List. Apart from the unethical aspect of doping, as it abrogates fair-play's principle, it is extremely important to consider the hazards it presents to the health and well-being of athletes. The referred negative effects for the athlete's health have to do, on the one hand, by the high doses of the performance-enhancing agents and on the other hand, by the relentless, superhuman strict training that the elite or amateur athletes put their muscles, bones, and joints. The purpose of this article is to highlight the early and the long-lasting consequences of the doping abuse on bone and muscle metabolism. © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique

Suppression of interleukin-1β and tumour necrosis factor-α biosynthesis by cadmium in in vitro activated human peripheral blood mononuclear cells

Cadmium is a highly toxic element responsible for acute and chronic toxicity in man. There is evidence that cadmium induces pathophysiological effects by modulating components of the immune system. Cytokines are being increasingly recognized as essential mediators of normal and pathologic immune responses. Cadmium at concentrations varying from 1.0×10-4 to 3.3×10-6 M inhibited the phytohemagglutinin induced production of interleukin-1β and tumour necrosis factor-α, in in vitro activated human peripheral blood mononuclear cells. The messenger RNA levels of interleukin-1β and tumour necrosis factor-α were examined during a 24-h culture period, at different time points. The decreased messenger RNA levels at the time points of the maximum expression of interleukin-1β and tumour necrosis factor-α indicate that cadmium suppresses their production at the transcriptional level. © 1994 Springer-Verlag

Focal adhesion kinase: A promising target for anticancer therapy

Focal adhesion kinase (FAK) is a protein tyrosine kinase acting as an early modulator of the integrin signalling cascade, thus regulating various basic cellular functions. In transformed cells, upregulation of FAK protein expression and uncontroled signalling were held responsible for the promotion of malignant phenotypic characteristics, as well as resistance to chemotherapy and radiotherapy. Direct FAK targeting resulted in the inhibition of the malignant phenotype of cancer cells, whereas increased apoptotic rates of cancer cells, either used alone or in combination with conventional chemotherapeutic agents, radiotherapy or hormonal therapy. Furthermore, drugs used in cancer chemotherapy, besides their basic mode of action, were also shown to act through altering FAK signalling. Finally, positive results were noted bythe transfection of cancer cells with fak mutants or genes that suppress FAK expression or activity, such as phosphatase and tensin homolog deleted on chromosome Ten (PTEN), ribonucleotide reductase M1 polypeptide (RRM1) and melanoma differentiation-associated gene-7 (mda-7). The purpose of this article is a comprehensive review of the existing data on the possible use of FAK targeting in anticancer therapy. © 2007 Informa UK Ltd

Metallothionein: A multifunctional protein from toxicity to cancer

The metallothionein (MT) family is a class of low molecular weight, intracellular and cysteine-rich proteins presenting high affinity for metal ions. Although the members of this family were discovered nearly 40 years ago, their functional significance remains obscure. Four major MT isoforms, MT-1, MT-2, MT-3 and MT-4, have been identified in mammals. MTs are involved in many pathophysiological processes such as metal ion homeostasis and detoxification, protection against oxidative damage, cell proliferation and apoptosis, chemoresistance and radiotherapy resistance. MT isoforms have been shown to be involved in several aspects of the carcinogenic process, cancer development and progression. MT expression has been implicated as a transient response to any form of stress or injury providing cytoprotective action. Although MT participates in the carcinogenic process, its use as a potential marker of tumor differentiation or cell proliferation, or as a predictor of poor prognosis remains unclear. In the present review the involvement of MT in defense mechanisms to toxicity and in carcinogenicity is discussed

Application of metabonomics on an experimental model of fibrosis and cirrhosis induced by thioacetamide in rats

Metabonomics has already been used to discriminate different pathological states in biological fields. The metabolic profiles of chronic experimental fibrosis and cirrhosis induction in rats were investigated using 1H NMR spectroscopy of liver extracts and serum combined with pattern recognition techniques. Rats were continuously administered with thioacetamide (TAA) in the drinking water (300 mg TAA/L), and sacrificed on 1st, 2nd, and 3rd month of treatment. 1H NMR spectra of aqueous and lipid liver extracts, together with serum were subjected to Principal Component Analysis (PCA). Liver portions were also subjected to histopathological examination and biochemical determination of malondialdehyde (MDA). Liver fibrosis and cirrhosis were progressively induced in TAA-treated rats, verified by the histopathological examination and the alterations of MDA levels. TAA administration revealed a number of changes in the 1H NMR spectra compared to control samples. The performance of PCA in liver extracts and serum, discriminated the control samples from the fibrotic and cirrhotic ones. Metabolic alterations revealed in NMR spectra during experimental liver fibrosis and cirrhosis induction, characterize the stage of fibrosis and could be illustrated by subsequent PCA of the spectra. Additionally, the PCA plots of the serum samples presented marked clustering during fibrosis progression and could be extended in clinical diagnosis for the management of cirrhotic patients. © 2006 Elsevier Inc. All rights reserved

Disruption of FAK signaling: A side mechanism in cytotoxicity

Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase (PTK) which acts as an early modulator in the integrin signaling cascade. FAK phosphorylation and its consequent activation regulate several basic biological cellular functions. On the contrary, dysregulation of FAK signaling is implicated in the malignant transformation of cells, as well as in nonmalignant pathological conditions. With respect to cytotoxicity, accumulating data indicate that FAK participates in the mechanism of action of the known cytotoxic reactive oxygen species (ROS). Additionally, evidence was presented that different cytotoxic substances, such as arsenic (As), lead (Pb), acrylamide, methylisothiazolinone (MIT), dichlorovinylcysteine (DCVC) and halothane, acted, at least in part, by downregulating FAK tyrosine phosphorylation, while the bacterial toxins Pasteurella multocida toxin and Escherichia coli cytotoxic necrotizing factor, have been shown to exert cytotoxic effects by inducing FAK tyrosine phosphorylation. The observation that upregulation as well as downregulation of FAK activity both result in cytotoxic effects seems contradictory. Even though a common mode of action, with respect to the dysregulation of FAK signaling, for these cytotoxic substances has not yet been discovered, a cumulative approach could be established by focusing on FAK activation and signaling cascade. According to these data, interfering with FAK signaling might be of a potential use in blocking these cytotoxic effects. Further studies are needed on the possible implication of FAK in substance-induced cytotoxicity, as well as the possibility that such effects might be hindered or even blocked by restoring FAK signaling. © 2007 Elsevier Ireland Ltd. All rights reserved

The role of endocannabinoids in pain modulation

The endocannabinoid system (ES) is comprised of cannabinoid (CB) receptors, their endogenous ligands (endocannabinoids), and proteins responsible for their metabolism. Endocannabinoids serve as retrograde signaling messengers in GABAergic and glutamatergic synapses, as well as modulators of postsynaptic transmission, that interact with other neurotransmitters. Physiological stimuli and pathological conditions lead to differential increases in brain endocannabinoids that regulate distinct biological functions. Furthermore, endocannabinoids modulate neuronal, glial, and endothelial cell function and exert neuromodulatory, anti-excitotoxic, anti-inflammatory, and vasodilatory effects. Analgesia is one of the principal therapeutic targets of cannabinoids. Cannabinoid analgesia is based on the suppression of spinal and thalamic nociceptive neurons, but peripheral sites of action have also been identified. The chronic pain that occasionally follows peripheral nerve injury differs fundamentally from inflammatory pain and is an area of considerable unmet therapeutic need. Over the last years, considerable progress has been made in understanding the role of the ES in the modulation of pain. Endocannabinoids have been shown to behave as analgesics in models of both acute nociception and clinical pain such as inflammation and painful neuropathy. The framework for such analgesic effects exists in the CB receptors, which are found in areas of the nervous system important for pain processing and in immune cells that regulate the neuro-immune interactions that mediate the inflammatory hyperalgesia. The purpose of this review is to present the available research and clinical data, up to date, regarding the ES and its role in pain modulation, as well as its possible therapeutic perspectives. © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique