12 results on '"Marquez AB"'
Search Results
2. Antiviral drug discovery: Pyrimidine entry inhibitors for Zika and dengue viruses.
- Author
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Gallo FN, Marquez AB, Fidalgo DM, Dana A, Dellarole M, García CC, and Bollini M
- Subjects
- Humans, Structure-Activity Relationship, Animals, Molecular Structure, Dose-Response Relationship, Drug, Microbial Sensitivity Tests, Virus Internalization drug effects, Chlorocebus aethiops, Vero Cells, Zika Virus drug effects, Dengue Virus drug effects, Antiviral Agents pharmacology, Antiviral Agents chemistry, Drug Discovery, Pyrimidines chemistry, Pyrimidines pharmacology
- Abstract
Vector-borne diseases, constituting over 17 % of infectious diseases, are caused by parasites, viruses, and bacteria, and their prevalence is shaped by environmental and social factors. Dengue virus (DENV) and Zika virus (ZIKV), some of the most prevalent infectious agents of this type of diseases, are transmitted by mosquitoes belonging to the genus Aedes. The highest prevalence is observed in tropical regions, inhabited by around 3 billion people. DENV infects millions of people annually and constitutes an additional sanitary challenge due to the circulation of four serotypes, which has complicated vaccine development. ZIKV causes large outbreaks globally and its infection is known to lead to severe neurological diseases, including microcephaly in newborns. Besides, not only mosquito control programs have proved to be not totally effective, but also, no antiviral drugs have been developed so far. The envelope protein (E) is a major component of DENV and ZIKV virion surface. This protein plays a key role during the virus cell entry, constituting an attractive target for the development of antiviral drugs. Our previous studies have identified two pyrimidine analogs (3e and 3h) as inhibitors; however, their activity was found to be hindered by their low water solubility. In this study, we performed a low-throughput antiviral screening, revealing compound 16a as a potent DENV-2 and ZIKV inhibitor (EC
50 = 1.4 μM and 2.4 μM, respectively). This work was aimed at designing molecules with improved selectivity and pharmacokinetic properties, thus advancing the antiviral efficacy of compounds for potential therapeutic use., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)- Published
- 2024
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3. Broad-Spectrum Antiviral Effect of Cannabidiol Against Enveloped and Nonenveloped Viruses.
- Author
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Marquez AB, Vicente J, Castro E, Vota D, Rodríguez-Varela MS, Lanza Castronuovo PA, Fuentes GM, Parise AR, Romorini L, Alvarez DE, Bueno CA, Ramirez CL, Alaimo A, and García CC
- Subjects
- Humans, Animals, Chlorocebus aethiops, Vero Cells, Zika Virus Infection drug therapy, Cell Line, Interferon-beta metabolism, Cannabidiol pharmacology, Antiviral Agents pharmacology, Zika Virus drug effects
- Abstract
Introduction: Cannabidiol (CBD), the main non-psychoactive cannabinoid of the Cannabis sativa plant, is a powerful antioxidant compound that in recent years has increased interest due to causes effects in a wide range of biological functions. Zika virus (ZIKV) is a virus transmitted mainly by the Aedes aegypti mosquitoes, which causes neurological diseases, such as microcephaly and Guillain-Barre syndrome. Although the frequency of viral outbreaks has increased recently, no vaccinations or particular chemotherapeutic treatments are available for ZIKV infection. Objectives: The major aim of this study was to explore the in vitro antiviral activity of CBD against ZIKV, expanding also to other dissimilar viruses. Materials and Methods: Cell cultures were infected with enveloped and nonenveloped viruses and treated with non-cytotoxic concentrations of CBD and then, viral titers were determined. Additionally, the mechanism of action of the compound during ZIKV in vitro infections was studied. To study the possible immunomodulatory role of CBD, infected and uninfected Huh-7 cells were exposed to 10 μM CBD during 48 h and levels of interleukins 6 and 8 and interferon-beta (IFN-β) expression levels were measured. On the other hand, the effect of CBD on cellular membranes was studied. For this, an immunofluorescence assay was performed, in which cell membranes were labeled with wheat germ agglutinin. Finally, intracellular cholesterol levels were measured. Results: CBD exhibited a potent antiviral activity against all the tested viruses in different cell lines with half maximal effective concentration values (CE50) ranging from 0.87 to 8.55 μM. Regarding the immunomodulatory effect of CBD during ZIKV in vitro infections, CBD-treated cells exhibited significantly IFN-β increased levels, meanwhile, interleukins 6 and 8 were not induced. Furthermore, it was determined that CBD affects cellular membranes due to the higher fluorescence intensity that was observed in CBD-treated cells and lowers intracellular cholesterol levels, thus affecting the multiplication of ZIKV and other viruses. Conclusions: It was demonstrated that CBD inhibits structurally dissimilar viruses, suggesting that this phytochemical has broad-spectrum antiviral effect, representing a valuable alternative in emergency situations during viral outbreaks, like the one caused by severe acute respiratory syndrome coronavirus 2 in 2020.
- Published
- 2024
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4. Design and characterization of BSA-mycophenolic acid nanocomplexes: Antiviral activity exploration.
- Author
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Castañeda Cataña MA, Dodes Traian MM, Rivas Marquina AP, Marquez AB, Arrúa EC, Carlucci MJ, Damonte EB, Pérez OE, and Sepúlveda CS
- Subjects
- Humans, Mycophenolic Acid, Molecular Docking Simulation, Virus Replication, Antiviral Agents pharmacology, Serum Albumin, Bovine, Junin virus
- Abstract
The interactions between bovine serum albumin (BSA) and mycophenolic acid (MPA) were investigated in silico through molecular docking and in vitro, using fluorescence spectroscopy. Dynamic light scattering and scanning electron microscopy were used to figure out the structure of MPA-Complex (MPA-C). The binding affinity between MPA and BSA was determined, yielding a Kd value of (12.0 ± 0.7) μM, and establishing a distance of 17 Å between the BSA and MPA molecules. The presence of MPA prompted protein aggregation, leading to the formation of MPA-C. The cytotoxicity of MPA-C and its ability to fight Junín virus (JUNV) were tested in A549 and Vero cell lines. It was found that treating infected cells with MPA-C decreased the JUNV yield and was more effective than free MPA in both cell line models for prolonged time treatments. Our results represent the first report of the antiviral activity of this type of BSA-MPA complex against JUNV, as assessed in cell culture model systems. MPA-C shows promise as a candidate for drug formulation against human pathogenic arenaviruses., Competing Interests: Declaration of competing interest Dr. Claudia S. Sepúlveda reports financial support was provided by National Scientific and Technical Research Council. Dr. Claudia S. Sepúlveda reports financial support was provided by National Agency for the Promotion of Research Technological Development and Innovation. Dr. Claudia S. Sepúlveda reports equipment, drugs, or supplies was provided by Novartis Pharmaceuticals Corporation. Dr. Elsa B. Damonte reports financial support was provided by University of Buenos Aires., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
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5. Vascularized 3D Human Skin Models in the Forefront of Dermatological Research.
- Author
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Rimal R, Muduli S, Desai P, Marquez AB, Möller M, Platzman I, Spatz J, and Singh S
- Subjects
- Animals, Humans, Skin, Neovascularization, Pathologic, Organoids, Tissue Engineering, Skin Diseases
- Abstract
In vitro engineered skin models are emerging as an alternative platform to reduce and replace animal testing in dermatological research. Despite the progress made in recent years, considerable challenges still exist for the inclusion of diverse cell types within skin models. Blood vessels, in particular, are essential in maintaining tissue homeostasis and are one of many primary contributors to skin disease inception and progression. Substantial efforts in the past have allowed the successful fabrication of vascularized skin models that are currently utilized for disease modeling and drugs/cosmetics testing. This review first discusses the need for vascularization within tissue-engineered skin models, highlighting their role in skin grafting and disease pathophysiology. Second, the review spotlights the milestones and recent progress in the fabrication and utilization of vascularized skin models. Additionally, advances including the use of bioreactors, organ-on-a-chip devices, and organoid systems are briefly explored. Finally, the challenges and future outlook for vascularized skin models are addressed., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)
- Published
- 2024
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6. RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy.
- Author
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Necarsulmer JC, Simon JM, Evangelista BA, Chen Y, Tian X, Nafees S, Marquez AB, Jiang H, Wang P, Ajit D, Nikolova VD, Harper KM, Ezzell JA, Lin FC, Beltran AS, Moy SS, and Cohen TJ
- Subjects
- Humans, Animals, Mice, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Disease Models, Animal, RNA, TDP-43 Proteinopathies genetics, TDP-43 Proteinopathies metabolism, Frontotemporal Lobar Degeneration genetics, Frontotemporal Lobar Degeneration metabolism, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics, Cognitive Dysfunction
- Abstract
TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic acid-binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed endogenous models of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43
K145Q resulted in stress-induced nuclear TDP-43 foci and loss of TDP-43 function in primary mouse and human-induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43K145Q mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of human FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies., Competing Interests: JN, JS, BE, YC, XT, SN, AM, HJ, PW, DA, VN, KH, JE, FL, AB, SM, TC No competing interests declared, (© 2023, Necarsulmer et al.)- Published
- 2023
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7. Effects of the Natural Flavonoid Quercetin on Arenavirus Junín Infection.
- Author
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Alvarez De Lauro AE, Pelaez MA, Marquez AB, Wagner MS, Scolaro LA, García CC, Damonte EB, and Sepúlveda CS
- Subjects
- Chlorocebus aethiops, Animals, Quercetin pharmacology, Flavonoids, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Vero Cells, Arenaviridae Infections, Arenavirus
- Abstract
There is no specific chemotherapy approved for the treatment of pathogenic arenaviruses that cause severe hemorrhagic fever (HF) in the population of endemic regions in America and Africa. The present study reports the effects of the natural flavonoid quercetin (QUER) on the infection of A549 and Vero cells with Junín virus (JUNV), agent of the Argentine HF. By infectivity assays, a very effective dose-dependent reduction of JUNV multiplication was shown by cell pretreatment at 2-6 h prior to the infection at non-cytotoxic concentrations, with 50% effective concentration values in the range of 6.1-7.5 µg/mL. QUER was also active by post-infection treatment but with minor efficacy. Mechanistic studies indicated that QUER mainly affected the early steps of virus adsorption and internalization in the multiplication cycle of JUNV. Treatment with QUER blocked the phosphorylation of Akt without changes in the total protein expression, detected by Western blot, and the consequent perturbation of the PI3K/Akt pathway was also associated with the fluorescence redistribution from membrane to cytoplasm of TfR1, the cell receptor recognized by JUNV. Then, it appears that the cellular antiviral state, induced by QUER treatment, leads to the prevention of JUNV entry into the cell.
- Published
- 2023
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8. Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis.
- Author
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Bashore FM, Marquez AB, Chaikuad A, Howell S, Dunn AS, Beltran AA, Smith JL, Drewry DH, Beltran AS, and Axtman AD
- Subjects
- Humans, Protein Serine-Threonine Kinases metabolism, Signal Transduction, Tubulin metabolism, Induced Pluripotent Stem Cells metabolism
- Abstract
Tau tubulin kinase 1 and 2 (TTBK1/2) are highly homologous kinases that are expressed and mediate disease-relevant pathways predominantly in the brain. Distinct roles for TTBK1 and TTBK2 have been delineated. While efforts have been devoted to characterizing the impact of TTBK1 inhibition in diseases like Alzheimer's disease and amyotrophic lateral sclerosis, TTBK2 inhibition has been less explored. TTBK2 serves a critical function during cilia assembly. Given the biological importance of these kinases, we designed a targeted library from which we identified several chemical tools that engage TTBK1 and TTBK2 in cells and inhibit their downstream signaling. Indolyl pyrimidinamine 10 significantly reduced the expression of primary cilia on the surface of human induced pluripotent stem cells (iPSCs). Furthermore, analog 10 phenocopies TTBK2 knockout in iPSCs, confirming a role for TTBK2 in ciliogenesis., (© 2023. The Author(s).)
- Published
- 2023
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9. Modulation of the Aryl Hydrocarbon Receptor Signaling Pathway Impacts on Junín Virus Replication.
- Author
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Pelaez MA, Torti MF, Alvarez De Lauro AE, Marquez AB, Giovannoni F, Damonte EB, and García CC
- Subjects
- Animals, Humans, Argentina, Mammals, Receptors, Aryl Hydrocarbon genetics, Signal Transduction, Virus Replication, Arenaviridae, Junin virus
- Abstract
Junín virus (JUNV), a member of the family Arenaviridae , is the etiological agent of the Argentine hemorrhagic fever, an endemic disease in the rural region of Argentina lacking a specific chemotherapy. Aryl hydrocarbon receptor (AHR) is expressed in several mammalian tissues and has been indicated as a sensor of ligands from variable sources and a modulator of the cell immune response. Interestingly, recent studies have suggested that the activation or depression of the AHR signaling pathway may play a role in the outcome of diverse human viral infections. In the present report, the effect of the pharmacological modulation of AHR on JUNV in vitro infection was analyzed. An initial microarray screening showed that the AHR pathway was overexpressed in JUNV-infected hepatic cells. Concomitantly, the infection of Vero and Huh-7 cells with the JUNV strains IV4454 and Candid#1 was significantly inhibited in a dose-dependent manner by treatment with CH223191, a specific AHR antagonist, as detected by infectivity assays, real-time RT-PCR and immunofluorescence detection of viral proteins. Furthermore, the pro-viral role of AHR in JUNV infection appears to be independent of the IFN-I pathway. Our findings support the promising perspectives of the pharmacological modulation of AHR as a potential target for the control of AHF.
- Published
- 2023
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10. PCSK9 Imperceptibly Affects Chemokine Receptor Expression In Vitro and In Vivo.
- Author
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Sundararaman SS, Peters LJF, Nazir S, Marquez AB, Bouma JE, Bayasgalan S, Döring Y, and van der Vorst EPC
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- Animals, Atherosclerosis metabolism, Atherosclerosis pathology, Atherosclerosis veterinary, Cytokines blood, Cytokines genetics, Cytokines metabolism, Endothelial Cells cytology, Endothelial Cells metabolism, Humans, Leukocytes cytology, Leukocytes metabolism, Lipopolysaccharides pharmacology, Liver metabolism, Macrophages, Peritoneal cytology, Macrophages, Peritoneal drug effects, Macrophages, Peritoneal metabolism, Mice, Mice, Inbred C57BL, Myocytes, Smooth Muscle cytology, Myocytes, Smooth Muscle metabolism, Proprotein Convertase 9 blood, Proprotein Convertase 9 genetics, Receptors, Chemokine genetics, Proprotein Convertase 9 metabolism, Receptors, Chemokine metabolism
- Abstract
Proprotein convertase subtilin/kexin type 9 (PCSK9) is a protease secreted mainly by hepatocytes and in lesser quantities by intestines, pancreas, and vascular cells. Over the years, this protease has gained importance in the field of cardiovascular biology due to its regulatory action on the low-density lipoprotein receptor (LDLR). However, recently, it has also been shown that PCSK9 acts independent of LDLR to cause vascular inflammation and increase the severity of several cardiovascular disorders. We hypothesized that PCSK9 affects the expression of chemokine receptors, major mediators of inflammation, to influence cardiovascular health. However, using overexpression of PCSK9 in murine models in vivo and PCSK9 stimulation of myeloid and vascular cells in vitro did not reveal influences of PCSK9 on the expression of certain chemokine receptors that are known to be involved in the development and progression of atherosclerosis and vascular inflammation. Hence, we conclude that the inflammatory effects of PCSK9 are not associated with the here investigated chemokine receptors and additional research is required to elucidate which mechanisms mediate PCSK9 effects independent of LDLR.
- Published
- 2021
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11. 3-D vascularized breast cancer model to study the role of osteoblast in formation of a pre-metastatic niche.
- Author
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Rimal R, Desai P, Marquez AB, Sieg K, Marquardt Y, and Singh S
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- Cell Line, Tumor, Coculture Techniques, Female, Humans, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, Tumor Microenvironment, Neoplasm Metastasis, Neovascularization, Pathologic, Osteoblasts pathology, Triple Negative Breast Neoplasms blood supply
- Abstract
Breast cancer cells (BCCs) preferentially metastasize to bone. It is known that BCCs remotely primes the distant bone site prior to metastasis. However, the reciprocal influence of bone cells on the primary tumor is relatively overlooked. Here, to study the bone-tumor paracrine influence, a tri-cellular 3-D vascularized breast cancer tissue (VBCTs) model is engineered which comprised MDA-MB231, a triple-negative breast cancer cells (TNBC), fibroblasts, and endothelial cells. This is indirectly co-cultured with osteoblasts (OBs), thereby constituting a complex quad-cellular tumor progression model. VBCTs alone and in conjunction with OBs led to abnormal vasculature and reduced vessel density but enhanced VEGF production. A total of 1476 significantly upregulated and 775 downregulated genes are identified in the VBCTs exposed to OBs. HSP90N, CYCS, RPS27A, and EGFR are recognized as upregulated hub-genes. Kaplan Meier plot shows HSP90N to have a significant outcome in TNBC patient survivability. Furthermore, compared to cancer tissues without vessels, gene analysis recognized 1278 significantly upregulated and 566 downregulated genes in VBCTs. DKK1, CXCL13, C3 protein and BMP4 are identified to be downregulated hub genes in VBCTs. Together, a multi-cellular breast cancer model and culture protocols are established to study pre-metastatic events in the presence of OBs., (© 2021. The Author(s).)
- Published
- 2021
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12. Antiviral bioactivity of resveratrol against Zika virus infection in human retinal pigment epithelial cells.
- Author
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Russo CA, Torti MF, Marquez AB, Sepúlveda CS, Alaimo A, and García CC
- Subjects
- Antiviral Agents chemistry, Binding Sites, Cell Line, Cell Survival drug effects, Cells, Cultured, Drug Development, Epithelial Cells drug effects, Epithelial Cells virology, Humans, Ligands, Mitochondrial Dynamics drug effects, Models, Biological, Models, Molecular, Protein Binding, Resveratrol chemistry, Structure-Activity Relationship, Virus Replication drug effects, Zika Virus Infection drug therapy, Zika Virus Infection pathology, Zika Virus Infection virology, Antiviral Agents pharmacology, Resveratrol pharmacology, Retinal Pigment Epithelium drug effects, Retinal Pigment Epithelium virology, Zika Virus drug effects
- Abstract
Resveratrol (RES) is a polyphenol with increasing interest for its inhibitory effects on a wide variety of viruses. Zika virus (ZIKV) is an arbovirus which causes a broad spectrum of ophthalmological manifestations in humans. Currently there is no certified therapy or vaccine to treat it, thus it has become a major global health threat. Retinal pigment epithelium (RPE) is highly permissive and susceptible to ZIKV. This work explored the protective effects of RES on ZIKV-infected human RPE cells. RES treatment resulted in a significant reduction of infectious viral particles in infected male ARPE-19 and female hTERT-RPE1 cells. This protection was positively influenced by the action of RES on mitochondrial dynamics. Also, docking studies predicted that RES has a high affinity for two enzymes of the rate-limiting steps of pyrimidine and purine biosynthesis and viral polymerase. This evidence suggests that RES might be a potential antiviral agent to treat ZIKV-induced ocular abnormalities., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)
- Published
- 2021
- Full Text
- View/download PDF
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