Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies

Prostate cancer, as one of the most prevalent malignancies in males, exhibits an approximate 5-year survival rate of 95% in advanced stages. A myriad of molecular events and mutations, including the accumulation of oncometabolites, underpin the genesis and progression of this cancer type. Despite growing research demonstrating the pivotal role of oncometabolites in supporting various cancers, including prostate cancer, the root causes of their accumulation, especially in the absence of enzymatic mutations, remain elusive. Consequently, identifying a tangible therapeutic target poses a formidable challenge. In this review, we aim to delve deeper into the implications of oncometabolite accumulation in prostate cancer. We center our focus on the consequential epigenetic alterations and impacts on cancer stem cells, with the ultimate goal of outlining novel therapeutic strategies

Human erythroid differentiation requires VDAC1-mediated mitochondrial clearance

Erythroblast maturation in mammals is dependent on organelle clearance throughout terminal erythropoiesis. We studied the role of the outer mitochondrial membrane protein voltage-dependent anion channel-1 (VDAC1) in human terminal erythropoiesis. We show that short hairpin (shRNA)-mediated downregulation of VDAC1 accelerates erythroblast maturation. Thereafter, erythroblasts are blocked at the orthochromatic stage, exhibiting a significant decreased level of enucleation, concomitant with an increased cell death. We demonstrate that mitochondria clearance starts at the transition from basophilic to polychromatic erythroblast, and that VDAC1 downregulation induces the mitochondrial retention. In damaged mitochondria from non-erythroid cells, VDAC1 was identified as a target for Parkin-mediated ubiquitination to recruit the phagophore. Here, we showed that VDAC1 is involved in phagophore’s membrane recruitment regulating selective mitophagy of still functional mitochondria from human erythroblasts. These findings demonstrate for the first time a crucial role for VDAC1 in human erythroblast terminal differentiation, regulating mitochondria clearance.Fil: Moras, Martina. Universite de Paris; Francia. Institut National de Transfusion Sanguine; Francia. Laboratoire d’Excellence GR-Ex; FranciaFil: Hattab, Claude. Universite de Paris; Francia. Institut National de Transfusion Sanguine; Francia. Laboratoire d’Excellence GR-Ex; FranciaFil: Gonzalez Menendez, Pedro. Laboratoire d’Excellence GR-Ex; Francia. Université Montpellier II; Francia. Centre National de la Recherche Scientifique; FranciaFil: Fader Kaiser, Claudio Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Odontologia; ArgentinaFil: Dussiot, Michael. Universite de Paris; Francia. Laboratoire d’Excellence GR-Ex; FranciaFil: Larghero, Jerome. Hôpital Saint-Louis. Unité de Thérapie cellulaire; FranciaFil: Le Van Kim, Caroline. Universite de Paris; Francia. Institut National de Transfusion Sanguine; Francia. Laboratoire d’Excellence GR-Ex; FranciaFil: Kinet, Sandrina. Laboratoire d’Excellence GR-Ex; Francia. Université Montpellier II; Francia. Centre National de la Recherche Scientifique; FranciaFil: Taylor, Naomi. Laboratoire d’Excellence GR-Ex; Francia. Centre National de la Recherche Scientifique; Francia. Université Montpellier II; Francia. Center for Cancer Research; Estados UnidosFil: Lefevre, Sophie D.. Universite de Paris; Francia. Institut National de Transfusion Sanguine; Francia. Laboratoire d’Excellence GR-Ex; FranciaFil: Ostuni, Mariano. Universite de Paris; Francia. Institut National de Transfusion Sanguine; Francia. Laboratoire d’Excellence GR-Ex; Franci

The insecticides permethrin and chlorpyrifos show limited genotoxicity and no leukemogenic potential in human and murine hematopoietic stem progenitor cells

Altres ajuts: European Food and Safety Authority, EFSA.PRAS.2018.04-CT1; Consejo Nacional de Ciencia y Tecnología, CB-2012-01-183467; Centro de Investigación Biomédica en Red en Cáncer, PID2019-104695RBI00; Asociación Española Contra el Cáncer, AECC INVES211226MOLI

Postural control modulation during motor imagery tasks: A systematic review

The motor imagery (MI) has two strategies (kinesthetic and visual) and can be defined as an act to codify the mental rehearsal of an intended action, without executing it. Studying the execution of the movement, several researchers believe that the deep muscles of the trunk are activated before the agonist of the limbs, showing a motor neurophysiologic recruitment order.This behavior can be also seen during MI tasks as the postural control, because the postural control is inserted in the movement context. The aim was to investigate, by a systematic review, evidences of MI and the postural control on healthy subjects. The selected articles were searched on different databases, dated from 1985 to 2014.Twelve studies were selected regarding the MI and the postural control on healthy subjects. All articles using balance scale or those which were about clinical conditions were excluded. Data show that kinesthetic MI with high levels of vividness promotes major changes in the body oscillations when comparing with the visual MI. To date, the number of articles about this theme is limited and the results should be interpreted cautiousl

Calcium-dependent oligomerization of CAR proteins at cell membrane modulates ABA signaling

[EN] Regulation of ion transport in plants is essential for cell function. Abiotic stress unbalances cell ion homeostasis, and plants tend to readjust it, regulating membrane transporters and channels. The plant hormone abscisic acid (ABA) and the second messenger Ca2+ are central in such processes, as they are involved in the regulation of protein kinases and phosphatases that control ion transport activity in response to environmental stimuli. The identification and characterization of the molecular mechanisms underlying the effect of ABA and Ca2+ signaling pathways on membrane function are central and could provide opportunities for crop improvement. The C2-domain ABA-related (CAR) family of small proteins is involved in the Ca2+-dependent recruitment of the pyrabactin resistance 1/PYR1like (PYR/PYL) ABA receptors to the membrane. However, to fully understand CAR function, it is necessary to define a molecular mechanism that integrates Ca2+ sensing, membrane interaction, and the recognition of the PYR/PYL interacting partners. We present structural and biochemical data showing that CARs are peripheral membrane proteins that functionally cluster on the membrane and generate strong positive membrane curvature in a Ca2+-dependent manner. These features represent a mechanism for the generation, stabilization, and/or specific recognition of membrane discontinuities. Such structures may act as signaling platforms involved in the recruitment of PYR/PYL receptors and other signaling components involved in cell responses to stress.A.A. and J.A.M. thank the European Syncrotron Radiation Facility and EMBL for access to the synchrotron radiation source. This work was funded by Ministerio de Economia y Competitividad (MINECO) Grants BFU2014-59796-R (to A.A.), BFU2011-28184-C02 (to M.J.S.-B.), and BIO2014-52537-R (to P.L.R.) and Comunidad de Madrid Grant S2010/BMD-2457 (to A.A and M.M.). M.J.S.-B. is supported by Ramon y Cajal Contract RYC-2008-03449 from MINECO and M.D. by a fellowship from Senacyt-Ifarhu. Access to the High Throughput Crystallization facility at European Molecular Biology Laboratory (EMBL) Grenoble was supported by the European Community's Seventh Framework Programme through the Protein Production Platform project (P-CUBE) Grant 227764.Diaz, M.; Sanchez-Barrena, MJ.; Gonzalez Rubio, JM.; Rodríguez Solovey, LN.; Fernández, D.; Antoni-Alandes, R.; Yunta, C.... (2016). Calcium-dependent oligomerization of CAR proteins at cell membrane modulates ABA signaling. Proceedings of the National Academy of Sciences. 113(3):E396-E405. https://doi.org/10.1073/pnas.1512779113SE396E4051133Serrano, R., & Rodriguez-Navarro, A. (2001). 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Assessment of exposure to DDT and metabolites after indoor residual spraying through the analysis of thatch material from rural African dwellings

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.[Introduction] We report on the analysis of 4,4′-dichlorodiphenyltrichloroethane (4,4′-DDT) and its metabolites in thatch and branch samples constituting the wall materials of dwellings from South African subtropical areas. This approach was used to assess the exposure to DDT in the residents of the dwellings after indoor residual spraying (IRS) following recommended sanitation practices against malaria vectors.[Discussion] Examination of the distributions of DDT compounds (2,4′-DDT, 4,4′-DDT and its metabolites) in 43 dwellings from the area of Manhiça (Mozambique) has shown median concentrations of 19, 130, and 23 ng/g for 2,4′-DDT, 4,4′-DDT, and 4,4′-DDE, respectively, in 2007 when IRS implementation was extensive. The concentrations of these compounds at the onset of the IRS campaign (n = 48) were 5. 5, 47, and 2. 2 ng/g, respectively. The differences were statistically significant and showed an increase in the concentration of this insecticide and its metabolites. Calculation of 4,4′-DDT in the indoor air resulting from the observed concentrations in the wall materials led to the characteristic values of environments polluted with this insecticide. © 2011 The Author(s).Funding was received from MICINN (INMA G03/176, Consolider Ingenio GRACCIE, CSD2007-00067), CSIC (PIF06-053), and ArcRisk EU Project (FP7-ENV-2008-1-226534).Peer reviewe

Fungal endophytes from arid areas of Andalusia: high potential sources for antifungal and antitumoral agents

Native plant communities from arid areas present distinctive characteristics to survive in extreme conditions. The large number of poorly studied endemic plants represents a unique potential source for the discovery of novel fungal symbionts as well as host-specific endophytes not yet described. The addition of adsorptive polymeric resins in fungal fermentations has been seen to promote the production of new secondary metabolites and is a tool used consistently to generate new compounds with potential biological activities. A total of 349 fungal strains isolated from 63 selected plant species from arid ecosystems located in the southeast of the Iberian Peninsula, were characterized morphologically as well as based on their ITS/28S ribosomal gene sequences. The fungal community isolated was distributed among 19 orders including Basidiomycetes and Ascomycetes, being Pleosporales the most abundant order. In total, 107 different genera were identified being Neocamarosporium the genus most frequently isolated from these plants, followed by Preussia and Alternaria. Strains were grown in four different media in presence and absence of selected resins to promote chemical diversity generation of new secondary metabolites. Fermentation extracts were evaluated, looking for new antifungal activities against plant and human fungal pathogens, as well as, cytotoxic activities against the human liver cancer cell line HepG2. From the 349 isolates tested, 126 (36%) exhibited significant bioactivities including 58 strains with exclusive antifungal properties and 33 strains with exclusive activity against the HepG2 hepatocellular carcinoma cell line. After LCMS analysis, 68 known bioactive secondary metabolites could be identified as produced by 96 strains, and 12 likely unknown compounds were found in a subset of 14 fungal endophytes. The chemical profiles of the differential expression of induced activities were compared. As proof of concept, ten active secondary metabolites only produced in the presence of resins were purified and identified. The structures of three of these compounds were new and herein are elucidated.This work was supported by Fundación MEDINA and the Andalusian Government grant RNM-7987 ‘Sustainable use of plants and their fungal parasites from arid regions of Andalucía for new molecules useful for antifungals and neuroprotectors’

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum