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The activation of the innate immune response during HSV-1 infection stimulates several transcription factors, such as NF-κB and IRF3, which are critical regulators of IFN-β expression. The released IFN-β activates the ISGs, which encode antiviral effectors such as the PKR. We found that HSV-1 triggers an antiviral transcriptional response during viral replication by activating TBK1-IRF3-NF-κB network kinetically. In contrast, we reported that infected PKR−/− cells fail to activate the transcription of TBK1. Downstream, TBK1 was unable to activate the transcription of IRF3 and NF-κB. These data suggested that in PKR−/− cells, HSV-1 replication counteracts TBK1-IRF3-NF-κB network. In this scenario, a combined approach of gene knockout and gene silencing was used to determine how the lack of PKR facilitates HSV-1 replication. We reported that in HEp-2-infected cells, PKR can influence the TBK1-IRF3-NF-κB network, consequently interfering with viral replication. Otherwise, an abrogated PKR-mediated signaling sustains the HSV-1 replication. Our result allows us to add additional information on the complex HSV-host interaction network by reinforcing the concept of the PKR role in the innate response-related networks during HSV replication in an in vitro model.

The current emergency due to the worldwide spread of the COVID-19 caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a great concern for global public health. Already in the past, the outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle Eastern respiratory syndrome (MERS) in 2012 demonstrates the potential of coronaviruses to cross-species borders and further underlines the importance of identifying new-targeted drugs. An ideal antiviral agent should target essential proteins involved in the lifecycle of SARS-CoV. Currently, some HIV protease inhibitors (i.e., Lopinavir) are proposed for the treatment of COVID-19, although their effectiveness has not yet been assessed. The main protease (Mpro) provides a highly validated pharmacological target for the discovery and design of inhibitors. We identified potent Mpro inhibitors employing computational techniques that entail the screening of a Marine Natural Product (MNP) library. MNP library was screened by a hyphenated pharmacophore model, and molecular docking approaches. Molecular dynamics and re-docking further confirmed the results obtained by structure-based techniques and allowed this study to highlight some crucial aspects. Seventeen potential SARS-CoV-2 Mpro inhibitors have been identified among the natural substances of marine origin. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds could be bioactive is excellent.

Viral infections are responsible for several chronic and acute diseases in both humans and animals. Despite the incredible progress in human medicine, several viral diseases, such as acquired immunodeficiency syndrome, respiratory syndromes, and hepatitis, are still associated with high morbidity and mortality rates in humans. Natural products from plants or other organisms are a rich source of structurally novel chemical compounds including antivirals. Indeed, in traditional medicine, many pathological conditions have been treated using plant-derived medicines. Thus, the identification of novel alternative antiviral agents is of critical importance. In this review, we summarize novel phytochemicals with antiviral activity against human viruses and their potential application in treating or preventing viral disease.

Gene therapy is a promising approach for the treatment of several diseases, such as chronic or viral infections, inherited disorders, and cancer. The cellular internalization of exogenous nucleic acids (NA) requires efficient delivery vehicles to overcome their inherent pharmacokinetic drawbacks, e.g. electrostatic repulsions, enzymatic degradation, limited cellular uptake, fast clearance, etc. Nanotechnological advancements have enabled the use of polymer-based nanostructured biomaterials as safe and effective gene delivery systems, in addition to viral vector delivery methods. Among the plethora of polymeric nanoparticles (NPs), this review will provide a comprehensive and in-depth summary of the polyester-based nanovehicles, including poly(lactic-co-glycolic acid) (PLGA) and polylactic acid (PLA) NPs, used to deliver a variety of foreign NA, e.g. short interfering RNA (siRNA), messenger RNA (mRNA), and plasmid DNA (pDNA). The article will review the versatility of polyester-based nanocarriers including their recent application in the delivery of the clustered, regularly-interspaced, short palindromic repeats/Cas (CRISPR/Cas) genome editing system for treating gene-related diseases. The remaining challenges and future trend of the targeted delivery of this revolutionary genome-editing system will be discussed. Special attention will be given to the pivotal role of nanotechnology in tackling emerging infections such as coronavirus disease 2019 (COVID-19): ground-breaking mRNA vaccines delivered by NPs are currently used worldwide to fight the pandemic, pushing the boundaries of gene therapy. Keywords: PLGA, PLA, siRNA, CRISPR, COVID-19, CLAN

Due to their antimicrobial and antiviral activity potential in vitro, polyphenols are gaining a lot of attention from the pharmaceutical and healthcare industries. A novel antiviral and antimicrobial approach could be based on the use of polyphenols obtained from natural sources. Here, we tested the antibacterial and antiviral effect of a mix of polyphenols present in natural almond skin (NS MIX). The antimicrobial potential was evaluated against the standard American Type Culture Collection (ATCC) and clinical strains of Staphylococcus aureus, including methicillin-resistant (MRSA) strains, by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Herpes simplex virus type I was used for the antiviral assessment of NS MIX by plaque assay. Furthermore, we evaluated the expression of viral cascade antigens. NS MIX exhibited antimicrobial (MIC values of 0.31–1.25 mg/ml) and antiviral activity (decrease in the viral titer ** p < 0.01, and viral DNA accumulation * p < 0.05) against Staphylococcus aureus and HSV-1, respectively. Amongst the isolated compounds, the aglycones epicatechin and catechin showed the greatest activity against S. aureus ATCC 6538P (MIC values of 0.078–0.15 and 0.15 mg/ml, respectively), but were not active against all the other strains. These results could be used to develop novel products for topical use.

In recent years, great interest has been committed to the search for alternative clinical treatments for herpetic infections that reduce side effects, overcome drug resistance, and combat the intense inflammatory response triggered by viral infection. Pistachios ( Pistacia vera L. ) are known to contain polyphenols, pharmacologically active compounds with both immunomodulatory and antiviral activities. The present work investigates the antiviral properties of pistachio extracts against HSV-1 and their potential immunomodulatory effect on human monocytic cells, with a focus on NF-κB signaling. The RT2 Profiler PCR array was used to identify differential expression of chemokines during infection and pretreatment. We discovered that HSV-1 induces potent cytokine and chemokine activation in monocytes, and that this activation is significantly reduced by in vitro treatment with pistachio extracts. Our focus included CXCL10, CXCL11, CCL13, CCL2, CCL4, CCL13 and the receptor CMKLR1, which were particularly expressed after HSV-1 replication and downregulated by pretreatment with pistachio extracts. We further confirmed this inhibitory activity using zeaxanthin, a bioactive carotenoid found in pistachios, which has previously shown to inhibit HSV-1 replication in permissive cells. In addition, by blocking viral replication with phosphonoacetic acid (PAA), we demonstrated that in HSV-1-infected THP-1 cells, activation of CXCL10, CXCL11, CCL13, CCL2, CCL4, CCL13 and CMKLR1 was significantly downregulated, suggesting that chemokine activation is partially dependent on active HSV-1 replication. Lastly, using THP-1-dnIκBα cells, we have demonstrated that chemokine accumulation was correlated with HSV-1-induced NF-κB activation. Importantly, when neuronal (SH-SY5Y) and epithelial (HEp-2) cells were exposed to supernatants derived from pistachio extracts and zeaxanthin-treated infected THP-1 cells, we observed a significant reduction in the production of new HSV-1 viral progeny compared to the untreated infected THP-1 cells. In conclusion, the study highlights the use of pistachio extracts and zeaxanthin as a promising therapeutic approach against HSV-1. Notably, it offers valuable insights into the complex virus-host interaction, demonstrating how HSV-1 modulates the chemokine-mediated cell response, including CXCL10, CXCL11, CCL13, CCL2, and CCL4, and the receptor CMKLR1, to maintain a delicate balance with the host cell, thereby promoting viral persistence.

The HSV-1 tegument protein Us11 counteracts the antiviral defense mechanisms by precluding the host protein shutoff. Previous works demonstrated that Us11 prevents heat-and staurosporine-induced apoptosis and inhibits autophagy. Therefore, in the present study, we investigated the hypothesis that HSV-1, through Us11, could recruit caspase-8, a key enzyme regulating programmed cell death. We first show that HSV-1 promotes the accumulation of caspase-8-p18 active fragments in both semi permissive THP-1 cells and fully permissive HEp-2 cells to HSV-1 replication. Using a recombinant virus R3630 (ΔUs11/ΔUs12) and a plasmid encoding Us11-recombinant protein we have proven that Us11 promotes p18 accumulation, which does not trigger the apoptotic signaling. Additional, in an in vitro model, we demonstrated that Us11-recombinant protein induces caspase-8-p18 cleavage by physically interacting with the caspase-8 recombinant protein. Finally, we found that, during HSV-1 replication, activated-caspase-8 cleaves Atg3 protein to potentially block autophagy and support its replication.

The aim of the present research was to determine the effect of almond skin extracts on herpes simplex virus 1 (HSV-1) replication. Drug-resistant strains of HSV frequently develop following therapeutic treatment. Therefore, the discovery of novel anti-HSV drugs deserves great effort. Here, we tested both natural (NS) and blanched (BS) polyphenols-rich almond skin extracts against HSV-1. HPLC analysis showed that the prevalent compounds in NS and BS extracts contributing to their antioxidant activity were quercetin, epicatechin and catechin. Results of cell viability indicated that NS and BS extracts were not toxic to cultured Vero cells. Furthermore, NS extracts were more potent inhibitors of HSV-1 than BS extracts, and this trend was in agreement with different concentrations of flavonoids. The plaque forming assay, Western blot and real-time PCR were used to demonstrate that NS extracts were able to block the production of infectious HSV-1 particles. In addition, the viral binding assay demonstrated that NS extracts inhibited HSV-1 adsorption to Vero cells. Our conclusion is that natural products from almond skin extracts are an extraordinary source of antiviral agents and provide a novel treatment against HSV-1 infections.

Graphene-based materials are intriguing nanomaterials with applications ranging from nanotechnology-related devices to drug delivery systems and biosensing. Multifunctional graphene platforms were proposed for the detection of several typical biomarkers (i.e., circulating tumor cells, exosomes, circulating nucleic acids, etc.) in liquid biopsy, and numerous methods, including optical, electrochemical, surface-enhanced Raman scattering (SERS), etc., have been developed for their detection. Due to the massive advancements in biology, material chemistry, and analytical technology, it is necessary to review the progress in this field from both medical and chemical sides. Liquid biopsy is considered a revolutionary technique that is opening unexpected perspectives in the early diagnosis and, in therapy monitoring, severe diseases, including cancer, metabolic syndrome, autoimmune, and neurodegenerative disorders. Although nanotechnology based on graphene has been poorly applied for the rapid diagnosis of viral diseases, the extraordinary properties of graphene (i.e., high electronic conductivity, large specific area, and surface functionalization) can be also exploited for the diagnosis of emerging viral diseases, such as the coronavirus disease 2019 (COVID-19). This review aimed to provide a comprehensive and in-depth summarization of the contribution of graphene-based nanomaterials in liquid biopsy, discussing the remaining challenges and the future trend; moreover, the paper gave the first look at the potentiality of graphene in COVID-19 diagnosis.

Graphene-based nanomaterials exhibit exceptional physicochemical properties that facilitate a range of diverse biomedical applications, including liquid biopsy. In this study, graphene-based magnetic units, termed MAGU (MAGnetic Units), were specifically engineered for the selective isolation of exosomes. Total extracellular vesicles were first enriched using ultracentrifugation, followed by immunomagnetic capture of CD9+ exosomes. MAGU functionalized with anti-CD9 antibody (MAGU-anti-CD9) efficiently recovered a CD9-positive exosome subpopulation expressing canonical markers ALIX, CD147, TSG101, and Flotillin-1, thereby confirming selective isolation performance. To investigate viral associated signaling, 293T cells were transduced with SARS-CoV-2 spike pseudovirus. This pseudovirus was engineered to express the SARS-CoV-2 spike protein, enabling simulation of viral entry and assessment of potential alterations in the exosomal profile induced by viral binding. Exosomes released by pseudovirus-transduced 293T cells were analyzed and compared to those from non-transduced controls. The MAGU-anti-CD9 complex selectively isolated a defined subset of CD9-positive vesicles enriched in the multifunctional transmembrane glycoprotein CD147, which has been proposed as a cofactor in SARS-CoV-2 entry. Comprehensive molecular profiling of selectively captured exosome subpopulations is expected to further support the application of MAGU technology in virus–host interaction research and liquid-biopsy-based diagnostics.