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Your search keyword '"Ana Serna‐Gallego"' showing total 2 results
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2 results on '"Ana Serna‐Gallego"'

1. HIV-1-DNA/RNA and immunometabolism in monocytes: contribution to the chronic immune activation and inflammation in people with HIV-1Research in context

Author

Esperanza Muñoz-Muela, María Trujillo-Rodríguez, Ana Serna-Gallego, Abraham Saborido-Alconchel, Carmen Gasca-Capote, Ana Álvarez-Ríos, Ezequiel Ruiz-Mateos, Dmitri Sviridov, Andrew J. Murphy, Man K.S. Lee, Luis F. López-Cortés, and Alicia Gutiérrez-Valencia

Subjects
Immunological non-responders, Monocytes, HIV-1 reservoir, Immunometabolism, Immune activation and inflammation, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Among people living with HIV-1 (PHIV), immunological non-responders (INR) experience incomplete immune recovery despite suppressive antiretroviral treatment (ART), facing more severe non-AIDS events than immunological responders (IR) due to higher chronic immune activation and inflammation (cIA/I). We analyzed the HIV-1 reservoir and immunometabolism in monocytes as a source of cIA/I. Methods: Cross-sectional study in which 110 participants were enrolled: 25 treatment-naïve; 35 INR; 40 IR; and 10 healthy controls. Cell-associated HIV-1-DNA (HIV-DNA) and -RNA (HIV-RNA) were measured in FACS-isolated monocytes using digital droplet PCR. Intact, 5′ deleted, and 3′ deleted proviruses were quantified by the intact proviral DNA assay. Systemic inflammation, monocyte immunophenotype, and immunometabolism were characterized by immunoassays, flow cytometry, and real-time cellular bioenergetics measurements, respectively. Findings: Monocytes from INR harbor higher HIV-RNA and HIV-DNA levels than IR. HIV-RNA was found in 14/21 treatment-naïve [2512 copies/106 TBP (331–4666)], 17/33 INR [240 (148–589)], and 15/28 IR [144 (15–309)], correlating directly with sCD163, IP-10, GLUT1high cells and glucose uptake, and inversely with the CD4+/CD8+ ratio. HIV-DNA was identified in all participants with detectable HIV-RNA, with intact provirus in 9/12 treatment-naïve [13 copies/106 monocytes (7–44)], 8/14 INR [46 (18–67)], and 9/13 IR [9 (7–24)]. INR presented glucose metabolism alterations and mitochondrial impairment; decreased coupling efficiency and BHI, and increased mitochondrial dysfunction inversely correlating with the CD4+/CD8+ ratio. Interpretation: HIV-RNA, more than HIV-DNA, in monocytes and their altered metabolism are factors associated with the higher cIA/I that characterize INR. Funding: This work was supported by the European Regional Development Fund, ISCIII, grant PI20/01646. Other funding sources: Instituto de Salud Carlos III through the Subprogram Miguel Servet (CP19/00159) to AGV, PFIS contracts (FI19/00304) to EMM, (FI21/00165) to ASA, and (FI19/00083) to CGC, and a mobility grant (MV21/00103) to EMM, from the Ministerio de Ciencia e Innovación, Spain. AJM was granted by a CSL Centenary Award.

Published
2024
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2. Optimization of piperazine-derived ureas privileged structures for effective antiadenovirus agents

Author

José M. Vega-Pérez, José Antonio Marrugal-Lorenzo, Javier Sánchez-Céspedes, Francesca Aiello, Margarita Vega-Holm, Jaime Álvarez-Vidal, Caridad Díaz, Judith Berastegui-Cabrera, Fernando Iglesias-Guerra, José Pérez del Palacio, Jerónimo Pachón, Ana Serna-Gallego, Sarah Mazzotta, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Red Española de Investigación en Patología Infecciosa, European Commission, Spanish Adenovirus Network, Junta de Andalucía, and Ministero dell'Istruzione, dell'Università e della Ricerca

Subjects
Drug, Human cytomegalovirus, DNA Replication, medicine.drug_class, Cell Survival, media_common.quotation_subject, Microbial Sensitivity Tests, Pharmacology, 01 natural sciences, Antiviral Agents, Piperazines, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Transcription (biology), Drug Discovery, medicine, Humans, Urea, Adenovirus, Privileged structures, Cytotoxicity, IC50, 030304 developmental biology, media_common, Thiourea/urea piperazine derivatives, 0303 health sciences, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Chemistry, Antiviral drugs, Adenoviruses, Human, Organic Chemistry, DNA replication, virus diseases, General Medicine, medicine.disease, 0104 chemical sciences, Piperazine, A549 Cells, Antiviral drug
Abstract

In recent years, human adenovirus (HAdV) infections have shown a high clinical impact in both immunosuppressed and immunocompetent patients. The research into specific antiviral drugs for the treatment of HAdV infections in immunocompromised patients constitutes a principal objective for medicinal chemistry due to the lack of any specific secure drug to treat these infections. In this study, we report a small-molecule library (67 compounds) designed from an optimization process of piperazine-derived urea privileged structures and their biological evaluation: antiviral activity and cytotoxicity. The active compounds selected were further evaluated to gain mechanistic understanding for their inhibition. Twelve derivatives were identified that inhibited HAdV infections at nanomolar and low micromolar concentrations (IC50 from 0.6 to 5.1 μM) with low cytotoxicity. In addition, our mechanistic assays suggested differences in the way the derivatives exert their anti-HAdV activity targeting transcription, DNA replication and later steps in the HAdV replication cycle. Furthermore, eight of the 12 studied derivatives blocked human cytomegalovirus (HCMV) DNA replication at low micromolar concentrations. The data provided herein indicates that the 12 thiourea/urea piperazine derivatives studied may represent potential lead compounds for clinical evaluation and development of new anti-HAdV drugs., This work has been supported by Ministerio de Economía y Competitividad, Plan Estatal 2013–2016 Retos-Proyectos I + D + i (CTQ2016-78580-C2-2-R) and by Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009) – co-financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014–2020, the Instituto de Salud Carlos III(DTS17/00130) and the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT) grants. MVH also thanks Ministerio de Economía y Competitividad, Plan Estatal 2013–2016 Excelencia I + D + i (CTQ2016-78703-P). JSC is a researcher belonging to the program “Nicolás Monardes” (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía, Spain. FA thanks Dipartimento di Farmacia e Scienze della Salute e della Nutrizione-Dipartimento di Eccellenza MIUR L 232/2016". JAV thanks Junta de Andalucia (Contrato de Garantías Juveniles).

Published
2020

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