Molecular signaling of dioxins

Dioxin derivatives sustain a substantial and versatile toxicity in rodent species, which remains challenging to investigate in human. As exemplified by several recent environmental contaminations reported by the media, humans remain under the threat of being accidentally exposed to dioxins. Firstly, we will describe a molecular signaling pathway that explains mainly the toxic effects of dioxins. It involves a pair of proteins that display a “PAS” active domain: the Aryl-hydrocarbon Receptor (AHR) and its dimerization partner (Arnt). This active dimer transactivates the transcription of a battery of target genes. Nevertheless, their identification does not provide evidence for all toxic actions attributed to dioxins. Transgenic murine models have provided novel physiological and developmental links to this receptor dimer, which appears to be recruited by several dietary chemicals. A recent investigation exposed the connection, at the protein level, between the AHRdioxin pathway and the Estrogen Receptor pathway, thus providing a novel meaning to some puzzling estrogenic effects sustained by dioxin derivatives.Les congénères chimiques de la dioxine déterminent une toxicité considérable et polymorphe chez les rongeurs; son appréciation est plus délicate et confuse chez l'homme. De récents développements médiatiques rappellent que le risque d'exposition humaine est patent et que dans l'attente d'une connaissance plus approfondie des implications en biologie humaine, un légitime principe de précaution s'impose. Suivant une introduction de la problématique, une voie de signalisation moléculaire expliquant une majorité des effets toxiques des dioxines sera présentée. Elle implique deux protéines à domaine fonctionnel PAS: un récepteur activé par les dioxines (AHR) et son partenaire de dimérisation (Arnt). Ce complexe nucléaire transactive une batterie de gènes qui constituent les cibles des dioxines. Cependant leur inventaire actuel n'autorise pas la compréhension exhaustive de la toxicité des dioxines. Des modèles murins déficients permettent d'appréhender certaines fonctions physiologiques et développementales de ce complexe activé par les dioxines. On observe un accroisement des connaissances relatives aux ligands naturels de ce récepteur (molécules alimentaires). De très récentes investigations mettent en lumière l'imbrication de la signalétique moléculaire du AHR avec celle du récepteur aux oestrogènes (ER), expliquant l'origine des surprenants effets oestrogéno-mimétiques produits par les contaminants environnementaux de la famille des dioxines

Molecular cloning, gene structure and expression profile of two mouse peroxisomal 3-ketoacyl-CoA thiolase genes

BACKGROUND: In rats, two peroxisomal 3-ketoacyl-CoA thiolase genes (A and B) have been cloned, whereas only one thiolase gene is found in humans. The aim of this study was thus to clone the different mouse thiolase genes in order to study both their tissue expression and their associated enzymatic activity. RESULTS: In this study, we cloned and characterized two mouse peroxisomal 3-ketoacyl-CoA thiolase genes (termed thiolase A and B). Both thiolase A and B genes contain 12 exons and 11 introns. Using RNA extracted from mouse liver, we cloned the two corresponding cDNAs. Thiolase A and B cDNAs possess an open reading frame of 1272 nucleotides encoding a protein of 424 amino acids. In the coding sequence, the two thiolase genes exhibited ≈97% nucleotide sequence identity and ≈96% identity at the amino acid level. The tissue-specific expression of the two peroxisomal 3-ketoacyl-CoA thiolase genes was studied in mice. Thiolase A mRNA was mainly expressed in liver and intestine, while thiolase B mRNA essentially exhibited hepatic expression and weaker levels in kidney, intestine and white adipose tissue. Thiolase A and B expressions in the other tissues such as brain or muscle were very low though these tissues were chiefly involved in peroxisomal disorders. At the enzymatic level, thiolase activity was detected in liver, kidney, intestine and white adipose tissue but no significant difference was observed between these four tissues. Moreover, thiolase A and B genes were differently induced in liver of mice treated with fenofibrate. CONCLUSION: Two mouse thiolase genes and cDNAs were cloned. Their corresponding transcripts are mostly expressed in the liver of mice and are differently induced by fenofibrate

Issues and special features of animal health research

In the rapidly changing context of research on animal health, INRA launched a collective discussion on the challenges facing the field, its distinguishing features, and synergies with biomedical research. As has been declared forcibly by the heads of WHO, FAO and OIE, the challenges facing animal health, beyond diseases transmissible to humans, are critically important and involve food security, agriculture economics, and the ensemble of economic activities associated with agriculture. There are in addition issues related to public health (zoonoses, xenobiotics, antimicrobial resistance), the environment, and animal welfare

Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator

X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disease due to mutations in the ABCD1 (ALD) gene, encoding a peroxisomal ATP-binding cassette transporter (ALDP). Overexpression of adrenoleukodystrophy-related protein, an ALDP homologue encoded by the ABCD2 (adrenoleukodystrophy-related) gene, can compensate for ALDP deficiency. 4-Phenylbutyrate (PBA) has been shown to induce both ABCD2 expression and peroxisome proliferation in human fibroblasts. We show that peroxisome proliferation with unusual shapes and clusters occurred in liver of PBA-treated rodents in a PPARα-independent way. PBA activated Abcd2 in cultured glial cells, making PBA a candidate drug for therapy of X-ALD. The Abcd2 induction observed was partially PPARα independent in hepatocytes and totally independent in fibroblasts. We demonstrate that a GC box and a CCAAT box of the Abcd2 promoter are the key elements of the PBA-dependent Abcd2 induction, histone deacetylase (HDAC)1 being recruited by the GC box. Thus, PBA is a nonclassical peroxisome proliferator inducing pleiotropic effects, including effects at the peroxisomal level mainly through HDAC inhibition

Câncer de fígado: ameaça nova ou antiga para os jovens dos países em desenvolvimento?

Among the most frequent malignancies worldwide, hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death (1). Its incidence has doubled over the past two decades, with the greatest burden occurring in low- and middle-income countries. Malignant primary liver tumors are usually described as a pathology affecting mainly men older than 40 years with a cirrhotic liver; they have rarely been reported in younger people and usually, in those younger than 40, most commonly hepatoblastoma.Entre las neoplasias malignas más frecuentes del mundo, el carcinoma hepatocelular (CHC) es la segunda causa de muerte relacionada con el cáncer (1). Su incidencia se ha duplicado durante las dos últimas décadas y la mayor carga se produce en los países de ingresos bajos y medianos. Los tumores hepáticos primarios malignos suelen describirse como una patología que afecta principalmente a hombres mayores de 40 años con un hígado cirrótico; rara vez se han registrado en personas más jóvenes y normalmente, en menores de 40, lo más común es el hepatoblastoma.Entre as doenças malignas mais comuns no mundo inteiro, o carcinoma hepatocelular (HCC) é a segunda principal causa de morte relacionada ao câncer (1). Sua incidência dobrou nas últimas duas décadas, sendo que a maior carga ocorreu em países de baixa e média renda. Os tumores primários malignos do fígado são geralmente descritos como uma patologia que afeta principalmente homens acima de 40 anos de idade com fígado cirrótico; raramente foram relatados em pessoas mais jovens e geralmente, naqueles com menos de 40 anos, o mais comum é o hepatoblastoma

p53 regulates epithelial–mesenchymal transition through microRNAs targeting ZEB1 and ZEB2

By transactivating expression of miRNAs that repress expression of the ZEB1 and ZEB2 transcription factors, p53 inhibits the epithelial–mesenchymal transition

HCV Defective Genomes Promote Persistent Infection by Modulating the Viral Life Cycle

Defective interfering (DI) RNAs have been detected in several human viruses. HCV in-frame deletions mutants (IFDMs), missing mainly the envelope proteins, have been found in patient sera and liver tissues. IFDMs replicate independently and can be trans-packaged into infectious virions in the presence of full length viral genome. So far, their biological role is unclear. In this study, we have isolated and cloned IFDMs from sera samples and liver tissues of patients infected with HCV genotypes 1b, 2a, and 3a. IFDMs were present in up to 26% of samples tested. Using the in vitro HCV cell culture system, co-expression of the wild type (wt) HCV replicon with HCV IFDMs RNA resulted in increased HCV replication. Additionally, co-transfection of the HCV full length genome RNA and a defective mutant missing the envelope region led to increased viral release, collectively suggesting an important biological role for IFDMs in the virus life cycle. Recently, exosomes, masters of intercellular communication, have been implicated in the transport of HCV viral genomes. We report for the first time that exosomal RNA isolated from HCV sera samples contains HCV defective genomes. We also demonstrate that inhibition of exosomal biogenesis and release influences HCV viral replication. Overall, we provide evidence that the presence of HCV IFDMs affects both viral replication and release. IFDMs exploit exosomes as means of transport, a way to evade the immune system, to spread more efficiently and possibly maintain persistent infection