Publications by authors named "Marta De Angelis"

11 Publications

  • Page 1 of 1

System-oriented optimization of multi-target 2,6-diaminopurine derivatives: Easily accessible broad-spectrum antivirals active against flaviviruses, influenza virus and SARS-CoV-2.

Eur J Med Chem 2021 Jul 5;224:113683. Epub 2021 Jul 5.

Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124, Parma, Italy. Electronic address:

The worldwide circulation of different viruses coupled with the increased frequency and diversity of new outbreaks, strongly highlight the need for new antiviral drugs to quickly react against potential pandemic pathogens. Broad-spectrum antiviral agents (BSAAs) represent the ideal option for a prompt response against multiple viruses, new and re-emerging. Starting from previously identified anti-flavivirus hits, we report herein the identification of promising BSAAs by submitting the multi-target 2,6-diaminopurine chemotype to a system-oriented optimization based on phenotypic screening on cell cultures infected with different viruses. Among the synthesized compounds, 6i showed low micromolar potency against Dengue, Zika, West Nile and Influenza A viruses (IC = 0.5-5.3 μM) with high selectivity index. Interestingly, 6i also inhibited SARS-CoV-2 replication in different cell lines, with higher potency on Calu-3 cells that better mimic the SARS-CoV-2 infection in vivo (IC = 0.5 μM, SI = 240). The multi-target effect of 6i on flavivirus replication was also analyzed in whole cell studies (in vitro selection and immunofluorescence) and against isolated host/viral targets.
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http://dx.doi.org/10.1016/j.ejmech.2021.113683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255191PMC
July 2021

Intracellular Redox-Modulated Pathways as Targets for Effective Approaches in the Treatment of Viral Infection.

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

Department of Biomolecular Sciences, University of Urbino Carlo Bo, Via Saffi 2, 61029 Urbino (PU), Italy.

Host-directed therapy using drugs that target cellular pathways required for virus lifecycle or its clearance might represent an effective approach for treating infectious diseases. Changes in redox homeostasis, including intracellular glutathione (GSH) depletion, are one of the key events that favor virus replication and contribute to the pathogenesis of virus-induced disease. Redox homeostasis has an important role in maintaining an appropriate Th1/Th2 balance, which is necessary to mount an effective immune response against viral infection and to avoid excessive inflammatory responses. It is known that excessive production of reactive oxygen species (ROS) induced by viral infection activates nuclear factor (NF)-B, which orchestrates the expression of viral and host genes involved in the viral replication and inflammatory response. Moreover, redox-regulated protein disulfide isomerase (PDI) chaperones have an essential role in catalyzing formation of disulfide bonds in viral proteins. This review aims at describing the role of GSH in modulating redox sensitive pathways, in particular that mediated by NF-B, and PDI activity. The second part of the review discusses the effectiveness of GSH-boosting molecules as broad-spectrum antivirals acting in a multifaceted way that includes the modulation of immune and inflammatory responses.
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http://dx.doi.org/10.3390/ijms22073603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036776PMC
March 2021

Investigation of (Nees) Engl. Oil and Its Main Components for Antiviral Activity.

Pharmaceuticals (Basel) 2021 Mar 9;14(3). Epub 2021 Mar 9.

Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, p.le Aldo Moro 5, I-00185 Rome, Italy.

The resinous exudate produced by (Nees) Engl. is commonly known as true myrrh and has been used since antiquity for several medicinal applications. Hundreds of metabolites have been identified in the volatile component of myrrh so far, mainly sesquiterpenes. Although several efforts have been devoted to identifying these sesquiterpenes, the phytochemical analyses have been performed by gas-chromatography/mass spectrometry (GC-MS) where the high temperature employed can promote degradation of the components. In this work, we report the extraction of by supercritical CO, an extraction method known for the mild extraction conditions that allow avoiding undesired chemical reactions during the process. In addition, the analyses of myrrh oil and of its metabolites were performed by HPLC and GC-MS. Moreover, we evaluated the antiviral activity against influenza A virus of the myrrh extracts, that was possible to appreciate after the addition of vitamin E acetate (α-tocopheryl acetate) to the extract. Further, the single main bioactive components of the oil of commercially available were tested. Interestingly, we found that both furanodienone and curzerene affect viral replication by acting on different steps of the virus life cycle.
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http://dx.doi.org/10.3390/ph14030243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999460PMC
March 2021

Laccase-Catalyzed 1,4-Dioxane-Mediated Synthesis of Belladine -Oxides with Anti-Influenza A Virus Activity.

Int J Mol Sci 2021 Jan 29;22(3). Epub 2021 Jan 29.

Department of Ecology and Biology, University of Tuscia, 01100 Viterbo, Italy.

Belladine -oxides active against influenza A virus have been synthetized by a novel laccase-catalyzed 1,4-dioxane-mediated oxidation of aromatic and side-chain modified belladine derivatives. Electron paramagnetic resonance (EPR) analysis confirmed the role of 1,4-dioxane as a co-oxidant. The reaction was chemo-selective, showing a high functional-group compatibility. The novel belladine -oxides were active against influenza A virus, involving the early stage of the virus replication life cycle.
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http://dx.doi.org/10.3390/ijms22031337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866262PMC
January 2021

[There is no progress without school. Postgraduate specialization school completes the paradigm shift in palliative care.]

Authors:
Marta De Angelis

Recenti Prog Med 2020 11;111(11):647-651

Medico palliativista, responsabile clinico AGLAIA, Associazione per l'assistenza palliativa onlus, Spoleto (PG).

With the conversion of law decree no. 34 of 19 May 2020, bearing urgent measures concerning health, support to work and the economy, as well as social policies related to CoViD-19 epidemiological emergency, thanks to the approval of an amendment to legislative decree "Rilancio" signed by Giorgio Trizzino, the Specialization school in medicine and palliative care will be established starting from a.y. 2021-2022. Additionally, a course in pediatric palliative care will be introduced in pediatrics specialization schools. The news has been welcomed with enthusiasm by the scientific community and the main stakeholders, some of which have made a strong contribution to this result: the Italian Society for Palliative Care, the Italian Federation for Palliative Care, the Maruzza Levebvre d'Ovidio Foundation, as well as the many professionals, institutions, and NPOs that have been supporting for the past forty years the progress of palliative care in Italy. An assessment of the impact of such a measure and its effects entails due process and contextualization in different areas: first of all, that of demand and current supply, followed by the historical-cultural, the social, and the normative.
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http://dx.doi.org/10.1701/3474.34565DOI Listing
November 2020

Redox-Modulating Agents in the Treatment of Viral Infections.

Int J Mol Sci 2020 Jun 8;21(11). Epub 2020 Jun 8.

Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome, Italy.

Viruses use cell machinery to replicate their genome and produce viral proteins. For this reason, several intracellular factors, including the redox state, might directly or indirectly affect the progression and outcome of viral infection. In physiological conditions, the redox balance between oxidant and antioxidant species is maintained by enzymatic and non-enzymatic systems, and it finely regulates several cell functions. Different viruses break this equilibrium and induce an oxidative stress that in turn facilitates specific steps of the virus lifecycle and activates an inflammatory response. In this context, many studies highlighted the importance of redox-sensitive pathways as novel cell-based targets for therapies aimed at blocking both viral replication and virus-induced inflammation. In the review, we discuss the most recent findings in this field. In particular, we describe the effects of natural or synthetic redox-modulating molecules in inhibiting DNA or RNA virus replication as well as inflammatory pathways. The importance of the antioxidant transcription factor Nrf2 is also discussed. Most of the data reported here are on influenza virus infection. We believe that this approach could be usefully applied to fight other acute respiratory viral infections characterized by a strong inflammatory response, like COVID-19.
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http://dx.doi.org/10.3390/ijms21114084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312898PMC
June 2020

Erratum to "Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures".

Oxid Med Cell Longev 2019 18;2019:3712969. Epub 2019 Apr 18.

Istituto Superiore di Sanità, Center for Gender-Specific Medicine, Rome, Italy.

[This corrects the article DOI: 10.1155/2019/6452390.].
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http://dx.doi.org/10.1155/2019/3712969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501126PMC
April 2019

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures.

Oxid Med Cell Longev 2019 13;2019:6452390. Epub 2019 Feb 13.

Istituto Superiore di Sanità, Center for Gender-Specific Medicine, Rome, Italy.

Hepatitis C virus (HCV) is a blood-borne pathogen causing acute and chronic hepatitis. A significant number of people chronically infected with HCV develop cirrhosis and/or liver cancer. The pathophysiologic mechanisms of hepatocyte damage associated with chronic HCV infection are not fully understood yet, mainly due to the lack of an system able to recapitulate the stages of infection . Several studies underline that HCV virus replication depends on redox-sensitive cellular pathways; in addition, it is known that virus itself induces alterations of the cellular redox state. However, the exact interplay between HCV replication and oxidative stress has not been elucidated. In particular, the role of reduced glutathione (GSH) in HCV replication and infection is still not clear. We set up an system, based on low m.o.i. of Huh7.5 cell line with a HCV infectious clone (J6/JFH1), that reproduced the acute and persistent phases of HCV infection up to 76 days of culture. We demonstrated that the acute phase of HCV infection is characterized by the elevated levels of reactive oxygen species (ROS) associated in part with an increase of NADPH-oxidase transcripts and activity and a depletion of GSH accompanied by high rates of viral replication and apoptotic cell death. Conversely, the chronic phase is characterized by a reestablishment of reduced environment due to a decreased ROS production and increased GSH content in infected cells that might concur to the establishment of viral persistence. Treatment with the prooxidant auranofin of the persistently infected cultures induced the increase of viral RNA titer, suggesting that a prooxidant state could favor the reactivation of HCV viral replication that in turn caused cell damage and death. Our results suggest that targeting the redox-sensitive host-cells pathways essential for viral replication and/or persistence may represent a promising option for contrasting HCV infection.
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http://dx.doi.org/10.1155/2019/6452390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393922PMC
May 2019

Antiviral and Antioxidant Activity of a Hydroalcoholic Extract from L.

Oxid Med Cell Longev 2018 24;2018:5919237. Epub 2018 Jul 24.

Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.

A hydroalcoholic extract from female inflorescences of L. (HOP extract) was evaluated for its anti-influenza activity. The ability of the extract to interfere with different phases of viral replication was assessed, as well as its effect on the intracellular redox state, being unbalanced versus the oxidative state in infected cells. The radical scavenging power, inhibition of lipoperoxidation, and ferric reducing activity were assayed as antioxidant mechanisms. A phytochemical characterization of the extract was also performed. We found that HOP extract significantly inhibited replication of various viral strains, at different time from infection. Viral replication was partly inhibited when virus was incubated with extract before infection, suggesting a direct effect on the virions. Since HOP extract was able to restore the reducing conditions of infected cells, by increasing glutathione content, its antiviral activity might be also due to an interference with redox-sensitive pathways required for viral replication. Accordingly, the extract exerted radical scavenging and reducing effects and inhibited lipoperoxidation and the tBOOH-induced cytotoxicity. At phytochemical analysis, different phenolics were identified, which altogether might contribute to HOP antiviral effect. In conclusion, our results highlighted anti-influenza and antioxidant properties of HOP extract, which encourage further studies to evaluate its possible application.
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http://dx.doi.org/10.1155/2018/5919237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081516PMC
October 2018

Differential Redox State Contributes to Sex Disparities in the Response to Influenza Virus Infection in Male and Female Mice.

Front Immunol 2018 30;9:1747. Epub 2018 Jul 30.

Department of Public Health and Infectious Diseases, Pasteur Institute Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy.

Influenza virus replicates intracellularly exploiting several pathways involved in the regulation of host responses. The outcome and the severity of the infection are thus strongly conditioned by multiple host factors, including age, sex, metabolic, and redox conditions of the target cells. Hormones are also important determinants of host immune responses to influenza and are recently proposed in the prophylaxis and treatment. This study shows that female mice are less susceptible than males to mouse-adapted influenza virus (A/PR8/H1N1). Compared with males, PR8-infected females display higher survival rate (+36%), milder clinical disease, and less weight loss. They also have milder histopathological signs, especially free alveolar area is higher than that in males, even if pro-inflammatory cytokine production shows slight differences between sexes; hormone levels, moreover, do not vary significantly with infection in our model. Importantly, viral loads (both in terms of viral M1 RNA copies and tissue culture infectious dose 50%) are lower in PR8-infected females. An analysis of the mechanisms contributing to sex disparities observed during infection reveals that the female animals have higher total antioxidant power in serum and their lungs are characterized by increase in (i) the content and biosynthesis of glutathione, (ii) the expression and activity of antioxidant enzymes (peroxiredoxin 1, catalase, and glutathione peroxidase), and (iii) the expression of the anti-apoptotic protein Bcl-2. By contrast, infected males are characterized by high expression of NADPH oxidase 4 oxidase and phosphorylation of p38 MAPK, both enzymes promoting viral replication. All these factors are critical for cell homeostasis and susceptibility to infection. Reappraisal of the importance of the host cell redox state and sex-related effects may be useful in the attempt to develop more tailored therapeutic interventions in the fight against influenza.
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http://dx.doi.org/10.3389/fimmu.2018.01747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077261PMC
September 2019

Antitumor Effects of Epidrug/IFNα Combination Driven by Modulated Gene Signatures in Both Colorectal Cancer and Dendritic Cells.

Cancer Immunol Res 2017 07 14;5(7):604-616. Epub 2017 Jun 14.

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

Colorectal cancer results from the progressive accumulation of genetic and epigenetic alterations. IFN signaling defects play an important role in the carcinogenesis process, in which the inability of IFN transcription regulatory factors (IRF) to access regulatory sequences in IFN-stimulated genes (ISG) in tumors and in immune cells may be pivotal. We reported that low-dose combination of two FDA-approved epidrugs, azacytidine (A) and romidepsin (R), with IFNα2 (ARI) hampers the aggressiveness of both colorectal cancer metastatic and stem cells and triggers immunogenic cell death signals that stimulate dendritic cell (DC) function. Here, we investigated the molecular signals induced by ARI treatment and found that this drug combination increased the accessibility to regulatory sequences of ISGs and IRFs that were epigenetically silenced in both colorectal cancer cells and DCs. Likewise, specific ARI-induced histone methylation and acetylation changes marked epigenetically affected ISG promoters in both metastatic cancer cells and DCs. Analysis by ChIP-seq confirmed such ARI-induced epigenetically regulated IFN signature. The activation of this signal endowed DCs with a marked migratory capability. Our results establish a direct correlation between reexpression of silenced ISGs by epigenetic control and ARI anticancer activity and provide new knowledge for the development of innovative combined therapeutic strategies for colorectal cancer. .
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http://dx.doi.org/10.1158/2326-6066.CIR-17-0080DOI Listing
July 2017