Publications by authors named "Jose Rueff"

The study of cancer, its initiation, and its mechanisms of progression has been a focal point in science for more than a century. Despite controversies among scientists, there is a growing consensus to determine the moment when a cell gains the capacity to be transformed and whether this mechanism is to be attributed to germinal or somatic events, or possibly both. The case of the Xavante Indians is a beacon for this journey, pointing toward the importance of genetic diversity in shaping our approach to cancer research and treatment.

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Progesterone receptor membrane component 1 (PGRMC1) is one of few proteins that have been recently described as direct modulators of the activity of human cytochrome P450 enzymes (CYP)s. These enzymes form a superfamily of membrane-bound hemoproteins that metabolize a wide variety of physiological, dietary, environmental, and pharmacological compounds. Modulation of CYP activity impacts the detoxification of xenobiotics as well as endogenous pathways such as steroid and fatty acid metabolism, thus playing a central role in homeostasis.

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control, muscle atrophy and in later stages, death. Diagnosis has an average delay of 1 year after symptoms onset, which impairs early management. The identification of a specific disease biomarker could help decrease the diagnostic delay.

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A unique cytochrome P450 (CYP) oxidoreductase (CPR) sustains activities of human microsomal CYPs. Its function requires toggling between a closed conformation enabling electron transfers from NADPH to FAD and then FMN cofactors and open conformations forming complexes and transferring electrons to CYPs. We previously demonstrated that distinct features of the hinge region linking the FAD and FMN domain (FD) modulate conformer poses and their interactions with CYPs.

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Familial Renal Glucosuria (FRG) is a co-dominantly inherited trait characterized by orthoglycaemic glucosuria. From 2003 to 2015 we have reported several cohorts validating SLC5A2 (16p11.2), encoding SGLT2 (Na+/glucose cotransporter family member 2), as the gene responsible for FRG.

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Genetic testing for susceptibility genes through next‑generation sequencing (NGS) has become a widely used technique. Using this, a number of genetic variants have been identified, several of which are variants of unknown significance (VUS). These VUS can either be pathogenic or benign.

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Genetic compositions of distinct human populations are different. How genomic variants influence many common and rare genetic diseases is always of great medical and anthropological interest, and understanding of genetic architectures of population groups in relation to diseases can advance our knowledge of medicine. Here, we have studied the genomic architecture of a group of Xavante Indians, an indigenous population in Brazil, and compared them with normal populations from the 1000 Genomes Projects.

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The altered activity of drug metabolism enzymes (DMEs) is a hallmark of chemotherapy resistance. Cytochrome P450s (CYPs), mainly CYP3A4, and several oxidoreductases are responsible for Phase I metabolism of doxorubicin (DOX), an anthracycline widely used in breast cancer (BC) treatment. This study aimed to investigate the role of Phase I DMEs involved in the first stages of acquisition of DOX-resistance in BC cells.

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In the last years, "omics" approaches have been applied to study the toxicity of nanomaterials (NM) with the aim of obtaining insightful information on their biological effects. One of the most developed "omics" field, transcriptomics, expects to find unique profiles of differentially-expressed genes after exposure to NM that, besides providing evidence of their mechanistic mode of action, may also be used as biomarkers for biomonitoring purposes. Moreover, several NM have been associated with epigenetic alterations, i.

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Human Cytochrome P450 (CYP) enzymes constitute a superfamily of membrane-bound hemoproteins that are responsible for the metabolism of a wide variety of clinically, physiologically, and toxicologically important compounds. These heme-thiolate monooxygenases play a pivotal role in the detoxification of xenobiotics, participating in the metabolism of many structurally diverge compounds. This short-review is intended to provide a summary on the major roles of CYPs in Phase I xenobiotic metabolism.

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Background: Breast cancer (BC) is the most common cancer in women. In contrast, male BC is about 100 times less common than in women, being considered a rare disease. Male BC may be a distinctive subtype of BC and available data seems to indicate that male BC has a higher dependence on genetic variants than female BC.

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Article Synopsis
  • Experimental and epidemiological studies indicate that lead exposure causes epigenetic changes, particularly affecting DNA methylation, chromatin structure, and non-coding RNA expression.
  • * The study aimed to explore how the expression of hsa-miR-148a influences DNA methylation status in 85 lead-exposed workers by measuring blood levels and miRNA expression.
  • * Results showed an inverse relationship between miR-148a expression and DNA methylation levels, suggesting that higher miR-148a is linked to lower DNA methylation in individuals exposed to lead.
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Radioiodine therapy with I remains the mainstay of standard treatment for well-differentiated thyroid cancer (DTC). Prognosis is good but concern exists that I-emitted ionizing radiation may induce double-strand breaks in extra-thyroidal tissues, increasing the risk of secondary malignancies. We, therefore, sought to evaluate the induction and 2-year persistence of micronuclei (MN) in lymphocytes from 26 I-treated DTC patients and the potential impact of nine homologous recombination (HR), non-homologous end-joining (NHEJ), and mismatch repair (MMR) polymorphisms on MN levels.

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The activity of microsomal cytochromes P450 (CYP) is strictly dependent on the supply of electrons provided by NADPH cytochrome P450 oxidoreductase (CPR). The variant nature of the isoform-specific proximal interface of microsomal CYPs implies that the interacting interface between the two proteins is degenerated. Recently, we demonstrated that specific CPR mutations in the FMN-domain (FD) may induce a gain in activity for a specific CYP isoform.

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Both copy number variations (CNVs) and chromothripsis are phenomena that involve complex genomic rearrangements. Chromothripsis results in CNVs and other structural changes. CNVs are frequently observed in the human genome.

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Cancer drug resistance (CDR) is a major problem in therapeutic failure. Over 90% of patients with metastatic cancer present CDR. Several mechanisms underlie CDR, including the increased expression of efflux ABC transporters and epigenetic phenomena.

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NADPH cytochrome P450 oxidoreductase (CPR) is the obligatory electron supplier that sustains the activity of microsomal cytochrome P450 (CYP) enzymes. The variant nature of the isoform-specific proximal interface of microsomal CYPs indicates that CPR is capable of multiple degenerated interactions with CYPs for electron transfer, through different binding mechanisms, and which are still not well-understood. Recently, we showed that CPR dynamics allows formation of open conformations that can be sampled by its structurally diverse redox partners in a CYP-isoform dependent manner.

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MicroRNAs (miRNAs), a group of small regulatory noncoding RNAs, transformed our thinking on gene regulation. More than two thousand human miRNAs have been identified thus far. These bind imperfectly to the 3'-untranslated region of target mRNA and have been involved in several pathological conditions including cancer.

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ABCB1 is a major player in cancer drug resistance. The purpose of this study was to functionally assess the regulation of ABCB1 activity in a doxorubicin-resistant breast cancer cell line by miR-200c and miR-203. Human breast carcinoma cell lines MCF-7 (Doxorubicin-sensitive and not expressing ABCB1) and KCR (Doxorubicin-resistant and expressing ABCB1) were used to evaluate the expression levels of miR-200c and miR-203 by Real-time quantitative PCR (RT-qPCR).

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The incidence of thyroid cancer (TC), particularly well-differentiated forms (DTC), has been rising and remains the highest among endocrine malignancies. Although ionizing radiation (IR) is well established on DTC aetiology, other environmental and genetic factors may also be involved. DNA repair single nucleotide polymorphisms (SNPs) could be among the former, helping in explaining the high incidence.

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NADPH-cytochrome P450 reductase (CPR) is the unique redox partner of microsomal cytochrome P450s (CYPs). CPR exists in a conformational equilibrium between open and closed conformations throughout its electron transfer (ET) function. Previously, we have shown that electrostatic and flexibility properties of the hinge segment of CPR are critical for ET.

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Several single nucleotide polymorphisms (SNPs) influencing DNA repair capacity and apoptotic status may confer genetic predisposition to Philadelphia‑chromosome negative myeloproliferative neoplasms (PN‑MPNs), and influence therapeutic response and the clinical course. In the present study, whether SNPs in genes involved in apoptosis and the base excision repair (BER) pathway was evaluated. In addition, some known risk factors in PN‑MPNs that may influence survival and therapeutic response to hydroxyurea (HU) were analyzed, taking into account three items: Disease progression, predisposition to new non‑myeloid neoplasms and thrombotic events.

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Cytochrome P450s (CYPs) are key enzymes involved in drug and xenobiotic metabolism. A wide array of in vitro methodologies, including recombinant sources, are currently been used to assess CYP catalysis, to identify the metabolic profile of compounds, potential drug-drug interactions, protein-protein interactions in the CYP enzyme complex and the role of polymorphic enzymes. We report here on a bacterial whole-cells high-throughput method for the activity evaluation of human CYP1A2, 2A6, and 3A4, when sustained by NADPH cytochrome P450 oxidoreductase (CPR), in the absence or presence of cytochrome b (CYB5).

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