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  1. Article ; Online: 131 I-C19 Iodide Radioisotope and Synthetic I-C19 Compounds as K-Ras4B–PDE6δ Inhibitors

    Pedro Cruz-Nova / Blanca Ocampo-García / Dayan Andrea Carrión-Estrada / Paola Briseño-Diaz / Guillermina Ferro-Flores / Nallely Jiménez-Mancilla / José Correa-Basurto / Martiniano Bello / Libia Vega-Loyo / María del Rocío Thompson-Bonilla / Rosaura Hernández-Rivas / Miguel Vargas

    Molecules, Vol 27, Iss 5446, p

    A Novel Approach against Colorectal Cancer—Biological Characterization, Biokinetics and Dosimetry

    2022  Volume 5446

    Abstract: In 40–50% of colorectal cancer (CRC) cases, K-Ras gene mutations occur, which induce the expression of the K-Ras4B oncogenic isoform. K-Ras4B is transported by phosphodiesterase-6δ (PDE6δ) to the plasma membrane, where the K-Ras4B–PDE6δ complex ... ...

    Abstract In 40–50% of colorectal cancer (CRC) cases, K-Ras gene mutations occur, which induce the expression of the K-Ras4B oncogenic isoform. K-Ras4B is transported by phosphodiesterase-6δ (PDE6δ) to the plasma membrane, where the K-Ras4B–PDE6δ complex dissociates and K-Ras4B, coupled to the plasma membrane, activates signaling pathways that favor cancer aggressiveness. Thus, the inhibition of the K-Ras4B–PDE6δ dissociation using specific small molecules could be a new strategy for the treatment of patients with CRC. This research aimed to perform a preclinical proof-of-concept and a therapeutic potential evaluation of the synthetic I-C19 and 131 I-C19 compounds as inhibitors of the K-Ras4B–PDE6δ dissociation. Molecular docking and molecular dynamics simulations were performed to estimate the binding affinity and the anchorage sites of I-C19 in K-Ras4B–PDE6δ. K-Ras4B signaling pathways were assessed in HCT116, LoVo and SW620 colorectal cancer cells after I-C19 treatment. Two murine colorectal cancer models were used to evaluate the I-C19 therapeutic effect. The in vivo biokinetic profiles of I-C19 and 131 I-C19 and the tumor radiation dose were also estimated. The K-Ras4B–PDE6δ stabilizer, 131 I-C19, was highly selective and demonstrated a cytotoxic effect ten times greater than unlabeled I-C19. I-C19 prevented K-Ras4B activation and decreased its dependent signaling pathways. The in vivo administration of I-C19 (30 mg/kg) greatly reduced tumor growth in colorectal cancer. The biokinetic profile showed renal and hepatobiliary elimination, and the highest radiation absorbed dose was delivered to the tumor (52 Gy/74 MBq). The data support the idea that 131 I-C19 is a novel K-Ras4B/PDE6δ stabilizer with two functionalities: as a K-Ras4B signaling inhibitor and as a compound with radiotherapeutic activity against colorectal tumors.
    Keywords I-C19 ; colorectal cancer ; K-Ras4B ; PDE6δ ; pharmacokinetics ; Organic chemistry ; QD241-441
    Subject code 333
    Language English
    Publishing date 2022-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: p21-Activated Kinase 1 Promotes Breast Tumorigenesis via Phosphorylation and Activation of the Calcium/Calmodulin-Dependent Protein Kinase II

    Héctor I. Saldivar-Cerón / Olga Villamar-Cruz / Claire M. Wells / Ibrahim Oguz / Federica Spaggiari / Jonathan Chernoff / Genaro Patiño-López / Sara Huerta-Yepez / Mayra Montecillo-Aguado / Clara M. Rivera-Pazos / Marco A. Loza-Mejía / Alonso Vivar-Sierra / Paola Briseño-Díaz / Alejandro Zentella-Dehesa / Alfonso Leon-Del-Rio / Alejandro López-Saavedra / Laura Padierna-Mota / María de Jesús Ibarra-Sánchez / José Esparza-López /
    Rosaura Hernández-Rivas / Luis E. Arias-Romero

    Frontiers in Cell and Developmental Biology, Vol

    2022  Volume 9

    Abstract: p21-Activated kinase-1 (Pak1) is frequently overexpressed and/or amplified in human breast cancer and is necessary for transformation of mammary epithelial cells. Here, we show that Pak1 interacts with and phosphorylates the Calcium/Calmodulin-dependent ... ...

    Abstract p21-Activated kinase-1 (Pak1) is frequently overexpressed and/or amplified in human breast cancer and is necessary for transformation of mammary epithelial cells. Here, we show that Pak1 interacts with and phosphorylates the Calcium/Calmodulin-dependent Protein Kinase II (CaMKII), and that pharmacological inhibition or depletion of Pak1 leads to diminished activity of CaMKII. We found a strong correlation between Pak1 and CaMKII expression in human breast cancer samples, and combined inhibition of Pak1 and CaMKII with small-molecule inhibitors was synergistic and induced apoptosis more potently in Her2 positive and triple negative breast cancer (TNBC) cells. Co-adminstration of Pak and CaMKII small-molecule inhibitors resulted in a dramatic reduction of proliferation and an increase in apoptosis in a 3D cell culture setting, as well as an impairment in migration and invasion of TNBC cells. Finally, mice bearing xenografts of TNBC cells showed a significant delay in tumor growth when treated with small-molecule inhibitors of Pak and CaMKII. These data delineate a signaling pathway from Pak1 to CaMKII that is required for efficient proliferation, migration and invasion of mammary epithelial cells, and suggest new therapeutic strategies in breast cancer.
    Keywords kinase ; migration ; small molecule inhibitor ; synergy ; breast cancer ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: The Plasmodium falciparum translationally controlled tumor protein (TCTP) is incorporated more efficiently into B cells than its human homologue.

    Berenice Calderón-Pérez / Beatriz Xoconostle-Cázares / Rosalía Lira-Carmona / Rosaura Hernández-Rivas / Jaime Ortega-López / Roberto Ruiz-Medrano

    PLoS ONE, Vol 9, Iss 1, p e

    2014  Volume 85514

    Abstract: Plasmodium falciparum secretes a homologue of the translationally controlled tumor protein (TCTP) into serum of infected individuals, although its role in pathogenesis or virulence is unknown. To determine the effect of P. falciparum TCTP on B cells as ... ...

    Abstract Plasmodium falciparum secretes a homologue of the translationally controlled tumor protein (TCTP) into serum of infected individuals, although its role in pathogenesis or virulence is unknown. To determine the effect of P. falciparum TCTP on B cells as compared to human TCTP, fluorescently labeled proteins were incubated on primary cultures of mouse splenic B cells and analyzed by flow cytometry and confocal microscopy. Our results indicate that both recombinant proteins are incorporated into B cells, but differ significantly in their rate and percentage of incorporation, being significantly higher for P. falciparum TCTP. Furthermore, P. falciparum TCTP showed a lower B cell proliferative effect than human TCTP, suggesting a mechanism through which the former could interfere in the host's immune response.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article: Identification of repressive and active epigenetic marks and nuclear bodies in Entamoeba histolytica

    Lozano-Amado, Daniela / Abril Marcela Herrera-Solorio / Jesús Valdés / Leticia Alemán-Lazarini / Ma. de Jesús Almaraz-Barrera / Eva Luna-Rivera / Miguel Vargas / Rosaura Hernández-Rivas

    Parasites & vectors. 2016 Dec., v. 9, no. 1

    2016  

    Abstract: BACKGROUND: In human hosts, Entamoeba histolytica cysts can develop into trophozoites, suggesting that the life cycle of this parasite are regulated by changes in gene expression. To date, some evidence has suggested that epigenetic mechanisms such as ... ...

    Abstract BACKGROUND: In human hosts, Entamoeba histolytica cysts can develop into trophozoites, suggesting that the life cycle of this parasite are regulated by changes in gene expression. To date, some evidence has suggested that epigenetic mechanisms such as DNA methylation and histone modification are involved in the regulation of gene expression in Entamoeba. Some post–translational modifications (PTMs) at the N-terminus of E. histolytica’s histones have been reported experimentally, including tri-methylation in the lysine 4 of histone H3 (H3K4me3) and dimethylation in the lysine 27 of histone H3 (H3K27me2), dimethylation of arginine 3 (H4R3me2) and the indirect acetylation of histone H4 in the N-terminal region. However, it is not known which residues of histone H4 are subject to acetylation and/or methylation or where in the nucleus these epigenetic marks are located. METHODS: Histones from trophozoites of E. histolytica were obtained and analyzed by LC-MS/MS. WB assays were performed using antibodies against epigenetic marks (acetylated lysines and methylated arginines). Immunofluorescence assays (IFA) were carried out to determine the distribution of PTMs and the localization of DNA methylation as a heterochromatin marker. Nuclear bodies such as the nucleolus were identified by using antibodies against fibrillarin and nucleolin and speckles by using anti-PRP6 antibody. RESULTS: Some new PTMs in histone H4 of E. histolytica, such as the acetylation of lysines 5, 8, 12 and 16 and the monomethylation of arginine 3, were identified by WB. IFA demonstrated that some marks are associated with transcriptional activity (such as acetylation and/or methylation) and that these marks are distributed throughout the E. histolytica nucleus. Staining with antibodies against anti-pan-acetylated lysine H4 histone and 5-methyl cytosine showed that the activation and transcriptional repression marks converge. Additionally, two nuclear bodies, the nucleolus and speckles, were identified in this parasite. CONCLUSIONS: This study provides the first evidence that the nucleus of E. histolytica is not compartmentalized and contains two nuclear bodies, the nucleolus and speckles, the latter of which was not identified previously. The challenge is now to understand how these epigenetic marks and nuclear bodies work together to regulate gene expression in E. histolytica.
    Keywords DNA methylation ; Entamoeba histolytica ; acetylation ; antibodies ; arginine ; cell nucleolus ; cytosine ; epigenetics ; fluorescent antibody technique ; gene expression ; heterochromatin ; histones ; hosts ; humans ; lysine ; parasites ; post-translational modification ; staining ; transcription (genetics) ; transcriptional activation ; trophozoites
    Language English
    Dates of publication 2016-12
    Size p. 19.
    Publishing place BioMed Central
    Document type Article
    ZDB-ID 2409480-8
    ISSN 1756-3305
    ISSN 1756-3305
    DOI 10.1186/s13071-016-1298-7
    Database NAL-Catalogue (AGRICOLA)

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  5. Article: Ribosomal RNA Genes in the Protozoan Parasite Leishmania major Possess a Nucleosomal Structure

    Vizuet-de-Rueda, Juan C / Luis E. Florencio-Martínez / Norma E. Padilla-Mejía / Rebeca Manning-Cela / Rosaura Hernández-Rivas / Santiago Martínez-Calvillo

    Protist. 2016 Apr., v. 167, no. 2

    2016  

    Abstract: Little is known about nucleosome structure and epigenetic regulation of transcription of rRNA genes in early-branched eukaryotes. Here we analyze the chromatin architecture and distribution of some histone modifications in the rRNA genes in the parasitic ...

    Abstract Little is known about nucleosome structure and epigenetic regulation of transcription of rRNA genes in early-branched eukaryotes. Here we analyze the chromatin architecture and distribution of some histone modifications in the rRNA genes in the parasitic protozoon Leishmania major. Southern blots of MNase-partially-digested chromatin with DNA probes spanning the whole rRNA gene repeat showed that the intergenic spacer presents a tight nucleosomal structure, whereas the promoter region is practically devoid of nucleosomes. Intermediate levels of nucleosomes were found in the rRNA coding regions. ChIP assays allowed us to determine that H3K14ac, H3K23ac and H3K27ac, epigenetics marks that are generally associated with activation of transcription, are enriched in the promoter region. In contrast, H4K20me3, which is generally related to transcriptional silencing, was absent from the promoter region and intergenic spacer and enriched in the coding region. Interestingly, the distribution pattern for H3K9me3, generally linked to heterochromatin formation, was very similar to the distribution observed with the euchromatin marks, suggesting that this modification could be involved in transcriptional activation of rRNA genes in L. major.
    Keywords DNA probes ; epigenetics ; eukaryotic cells ; genes ; heterochromatin ; histones ; intergenic DNA ; Leishmania major ; nucleosomes ; parasites ; promoter regions ; ribosomal RNA ; Southern blotting ; transcription (genetics) ; transcriptional activation
    Language English
    Dates of publication 2016-04
    Size p. 121-135.
    Publishing place Elsevier GmbH
    Document type Article
    ZDB-ID 2036014-9
    ISSN 1618-0941 ; 1434-4610
    ISSN (online) 1618-0941
    ISSN 1434-4610
    DOI 10.1016/j.protis.2016.02.001
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  6. Article ; Online: Separation and Mapping of Chromosomes of Parasitic Protozoa

    Rosaura Hernandez-Rivas / Artur Scherf

    Memórias do Instituto Oswaldo Cruz., Vol 92, Iss 6, p

    1997  Volume 815

    Abstract: Many protozoan parasites represent an important group of human pathogens. Pulsed Field Gradient Gel Electrophoresis (PFGE) analysis has been an important tool for fundamental genetic studies of parasites like Trypanosoma, Leishmania, Giardia or the human ...

    Abstract Many protozoan parasites represent an important group of human pathogens. Pulsed Field Gradient Gel Electrophoresis (PFGE) analysis has been an important tool for fundamental genetic studies of parasites like Trypanosoma, Leishmania, Giardia or the human malaria parasite Plasmodium falciparum. We present PFGE conditions allowing a high resolution separation of chromosomes ranging from 500 to 4000 kb within a two day electrophoresis run. In addition, we present conditions for separating large chromosomes (2000-6000 kb) within 36 hr. We demontrate that the application of two dimentional PFGE (2D-PFGE) technique to parasite karyotypes is a very useful method for the analysis of dispersed gene families and comparative studies of the intrachomosomal genome organization
    Keywords Pulsed Field Gradient Gel Electrophoresis ; two dimensional PFGE ; protozoan karyotypes ; chromosome mapping ; dispersed gene families ; Microbiology ; QR1-502 ; Science ; Q ; DOAJ:Microbiology ; DOAJ:Biology ; DOAJ:Biology and Life Sciences ; Arctic medicine. Tropical medicine ; RC955-962 ; Special situations and conditions ; RC952-1245 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Internal medicine ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
    Subject code 572
    Language English
    Publishing date 1997-11-01T00:00:00Z
    Publisher Instituto Oswaldo Cruz, Ministério da Saúde
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Separation and Mapping of Chromosomes of Parasitic Protozoa

    Rosaura Hernandez-Rivas / Artur Scherf

    Memórias do Instituto Oswaldo Cruz., Vol 92, Iss 6, Pp 815-

    1997  Volume 819

    Abstract: Many protozoan parasites represent an important group of human pathogens. Pulsed Field Gradient Gel Electrophoresis (PFGE) analysis has been an important tool for fundamental genetic studies of parasites like Trypanosoma, Leishmania, Giardia or the human ...

    Abstract Many protozoan parasites represent an important group of human pathogens. Pulsed Field Gradient Gel Electrophoresis (PFGE) analysis has been an important tool for fundamental genetic studies of parasites like Trypanosoma, Leishmania, Giardia or the human malaria parasite Plasmodium falciparum. We present PFGE conditions allowing a high resolution separation of chromosomes ranging from 500 to 4000 kb within a two day electrophoresis run. In addition, we present conditions for separating large chromosomes (2000-6000 kb) within 36 hr. We demontrate that the application of two dimentional PFGE (2D-PFGE) technique to parasite karyotypes is a very useful method for the analysis of dispersed gene families and comparative studies of the intrachomosomal genome organization
    Keywords Pulsed Field Gradient Gel Electrophoresis ; two dimensional PFGE ; protozoan karyotypes ; chromosome mapping ; dispersed gene families ; Arctic medicine. Tropical medicine ; RC955-962 ; Microbiology ; QR1-502
    Subject code 572
    Language English
    Publishing date 1997-11-01T00:00:00Z
    Publisher Instituto Oswaldo Cruz, Ministério da Saúde
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Telomeric Heterochromatin in Plasmodium falciparum

    Rosaura Hernandez-Rivas / Karla Pérez-Toledo / Abril-Marcela Herrera Solorio / Dulce María Delgadillo / Miguel Vargas

    Journal of Biomedicine and Biotechnology, Vol

    2010  Volume 2010

    Abstract: Until very recently, little was known about the chromatin structure of the telomeres and subtelomeric regions in Plasmodium falciparum. In yeast and Drosophila melanogaster, chromatin structure has long been known to be an important aspect in the ... ...

    Abstract Until very recently, little was known about the chromatin structure of the telomeres and subtelomeric regions in Plasmodium falciparum. In yeast and Drosophila melanogaster, chromatin structure has long been known to be an important aspect in the regulation and functioning of these regions. Telomeres and subtelomeric regions are enriched in epigenetic marks that are specific to heterochromatin, such as methylation of lysine 9 of histone H3 and lysine 20 of histone H4. In P. falciparum, histone modifications and the presence of both the heterochromatin “writing” (PfSir2, PKMT) and “reading” (PfHP1) machinery at telomeric and subtelomeric regions indicate that these regions are likely to have heterochromatic structure that is epigenetically regulated. This structure may be important for telomere functions such as the silencing of the var gene family implicated in the cytoadherence and antigenic variation of these parasites.
    Keywords Biotechnology ; TP248.13-248.65 ; Chemical technology ; TP1-1185 ; Technology ; T ; DOAJ:Biotechnology ; DOAJ:Life Sciences ; DOAJ:Biology and Life Sciences
    Language English
    Publishing date 2010-01-01T00:00:00Z
    Publisher Hindawi Publishing Corporation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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