Myrtus communis leaves: source of bio - actives, traditional use, their biological properties, and prospects / Hojas de Myrtus communis: fuente de bioactivos, uso tradicional, sus propiedades biológicas y perspectivas

Myrtus communis L., commonly known as true myrtle, is a medicinal plant native to the Mediterranean area. Since ancient times, the inhabitant s of this area have been using it for its cultural and medicinal properties. Because of the vast diversity of biomolecules in its aerial parts, it exhibits several biological properties, including antioxidant, antimicrobial, and anticancer properties. This review retrospect the research on the source, biological activities with empirical evidence, chemical composition, applications, and cellular targets of extracts and essential oils obtained from M. communis leaves, which provides a perspective for further studies on the applications and formulations of extract and EO of M. communis leaves. The efficacy of constituents' individually, in association with other bioactive constituents, or in combination with available commercial drugs would provide insights in to the development of these bio - actives as future drugs and their evolving future potential applications in the pharmaceutical, food, and aroma industries.

Myrtus communis L., comúnmente conocido como arrayán verdadero, es una planta medicinal originaria de la zona mediterránea. Desde la antigüedad, los habitantes de esta zona lo utilizan por sus propiedades culturales y medicinales. Debido a la gran div ersidad de biomoléculas en sus partes aéreas, exhibe varias propiedades biológicas, incluidas propiedades antioxidantes, antimicrobianas y anticancerígenas. Esta revisión retrospectiva de la investigación sobre la fuente, las actividades biológicas con evi dencia empírica, la composición química, las aplicaciones y los objetivos celulares de los extractos y aceites esenciales obtenidos de las hojas de M. communis , lo que brinda una perspectiva para futuros estudios sobre las aplicaciones y formulaciones de l os extractos y EO de M. communis . La eficacia de los componentes individualmente, en asociación con otros componentes bioactivos o en combinación con medicamentos comerciales disponibles proporcionaría información sobre el desarrollo de estos bioactivos co mo medicamentos futuros y sus futuras aplicaciones potenciales en las industrias farmacéutica, alimentaria y aromática

Molecular targets of cisplatin in HeLa cells explored through competitive activity-based protein profiling strategy.

Cisplatin is widely used as anticancer drugs, and DNA is considered as the main target. Considering its high affinity towards cysteines and the important role of cystine containing proteins, we applied a competitive activity-based protein profiling strategy to identify protein cysteines that bind with cisplatin in HeLa cells. Living cells were treated with cisplatin at cytotoxic concentrations, then the protein was extracted. After labeling with desthiobiotin iodoacetamide (DBIA) probe, protein was precipitated, digested and isotopically labeled, subsequently the peptides were combined, and the biotinylated cysteine-containing peptides were enriched and quantified by LC-MS/MS. A total of 3571 peptides which originated from 1871 proteins were identified using the DBIA probe. Among them, 46 proteins were screened as targets, including proteins that have been identified as binding proteins by previous study. A novel cisplatin target, calpain-1 (CAPN1), was identified and validated as binding with cisplatin in vitro.

Direct antimicrobial effects of chemokines on Cryptococcus spp, with special emphasis on a 'CXC' chemokine.

Cryptococcus species are ingenious human pathogens that are widespread globally. They continue to cause over 200,000 deaths per year. Presently due to the rise in resistance and therapy failure, it is necessary to shift the focus to an alternate therapeutic strategy against this pathogen. One promising approach is to emphasize the host defense system in order to develop more precise and customized treatment strategies. In this regard, research has revealed that interferon-γ-inducible CXCL10 chemokine, amongst other chemokines spanning both CXC and CC categories, has a direct killing effect in vitro against Cryptococcus neoformans and Cryptococcus gattii, with a significantly greater microbicidal effect against the former. Moreover, when CXCL10 is used in combination with CCL5, there is a significant reduction in the survival of C. gattii at normal-serum level concentration, indicating a previously unreported synergistic effect of these two chemokines. Confocal and STED microscopic studies have demonstrated that CXCL10 has both cell wall/membrane and intracellular targets against this fungus. These findings present new possibilities for developing chemokine-derived small molecule antifungals and may represent a step forward in creating precision medicine tailored to each patient.

Cooperation is the key: the CCN biological system as a gate to high complex protein superfamilies' signaling.

Cellular signaling is generally understood as the support of communication between contiguous cells belonging to the same tissue or cells being far apart of each other, at a molecular scale, when the message emitted by the transmitters is traveling in liquid or solid matter to reach recipient targets. Subcellular signaling is also important to ensure the proper cell constitution and functioning. However cell signaling is mostly used in the first understanding, to describe how the message sent from one point to another one, will reach a target where it will be interpreted. The Cellular Communication Network (CCN) factors (Perbal et al. 2018) constitute a family of biological regulators thought to be responsible for signaling pathways coordination (Perbal 2018). Indeed, these proteins interact with a diverse group of cell receptors, such as integrins, low density lipoprotein receptors, heparan sulfate proteoglycan receptors (HSPG), and the immunoglobulin superfamily expressed exclusively in the nervous system, or with soluble factors such as bone morphogenetic proteins (BMPS) and other growth factors such as vascular endothelial growth factor, fibroblastic growth factor, and transforming growth factor (TGFbeta). Starting from the recapitulation of basic concepts in enzymology and protein-ligands interactions, we consider, in this manuscript, interpretations of the mechanistic interactions that have been put forward to explain the diversity of CCN proteins biological activities. We suggest that the cross-talks between superfamilies of proteins under the control of CCNs might play a central role in the coordination of developmental signaling pathways.

Antifungal Compounds from Microbial Symbionts Associated with Aquatic Animals and Cellular Targets: A Review.

Fungal infections continue to be a serious public health problem, leading to an estimated 1.6 million deaths annually. It remains a major cause of mortality for people with a weak or affected immune system, such as those suffering from cancer under aggressive chemotherapies. On the other hand, pathogenic fungi are counted among the most destructive factors affecting crops, causing a third of all food crop losses annually and critically affecting the worldwide economy and food security. However, the limited number currently available and the cytotoxicity of the conventional antifungal drugs, which are not yet properly diversified in terms of mode of action, in addition to resistance phenomena, make the search for new antifungals imperative to improve both human health and food protection. Symbiosis has been a crucial alternative for drug discovery, through which many antimicrobials have been discovered. This review highlights some antifungal models of a defensive symbiosis of microbial symbiont natural products derived from interacting with aquatic animals as one of the best opportunities. Some recorded compounds with supposed novel cell targets such as apoptosis could lead to the development of a multitherapy involving the mutual treatment of fungal infections and other metabolic diseases involving apoptosis in their pathogenesis pathways.

Water-Soluble Carbon Monoxide-Releasing Molecules (CORMs).

Carbon monoxide-releasing molecules (CORMs) are promising candidates for producing carbon monoxide in the mammalian body for therapeutic purposes. At higher concentrations, CO has a harmful effect on the mammalian organism. However, lower doses at a controlled rate can provide cellular signaling for mandatory pharmacokinetic and pathological activities. To date, exploring the therapeutic implications of CO dose as a prodrug has attracted much attention due to its therapeutic significance. There are two different methods of CO insertion, i.e., indirect and direct exogenous insertion. Indirect exogenous insertion of CO suggests an advantage of reduced toxicity over direct exogenous insertion. For indirect exogenous insertion, researchers are facing the issue of tissue selectivity. To solve this issue, developers have considered the newly produced CORMs. Herein, metal carbonyl complexes (MCCs) are covalently linked with CO molecules to produce different CORMs such as CORM-1, CORM-2, and CORM-3, etc. All these CORMs required exogenous CO insertion to achieve the therapeutic targets at the optimized rate under peculiar conditions or/and triggering. Meanwhile, the metal residue was generated from i-CORMs, which can propagate toxicity. Herein, we explain CO administration, water-soluble CORMs, tissue accumulation, and cytotoxicity of depleted CORMs and the kinetic profile of CO release.

Superantigens, a Paradox of the Immune Response.

Staphylococcal enterotoxins are a wide family of bacterial exotoxins with the capacity to activate as much as 20% of the host T cells, which is why they were called superantigens. Superantigens (SAgs) can cause multiple diseases in humans and cattle, ranging from mild to life-threatening infections. Almost all S. aureus isolates encode at least one of these toxins, though there is no complete knowledge about how their production is triggered. One of the main problems with the available evidence for these toxins is that most studies have been conducted with a few superantigens; however, the resulting characteristics are attributed to the whole group. Although these toxins share homology and a two-domain structure organization, the similarity ratio varies from 20 to 89% among different SAgs, implying wide heterogeneity. Furthermore, every attempt to structurally classify these proteins has failed to answer differential biological functionalities. Taking these concerns into account, it might not be appropriate to extrapolate all the information that is currently available to every staphylococcal SAg. Here, we aimed to gather the available information about all staphylococcal SAgs, considering their functions and pathogenicity, their ability to interact with the immune system as well as their capacity to be used as immunotherapeutic agents, resembling the two faces of Dr. Jekyll and Mr. Hyde.

Molecular Features Triggered by Antipsychotic Medication in Brain Cells.

Treating schizophrenia is a challenge currently handled with the use of antipsychotic drugs. Despite being the most applied treatment strategy, current antipsychotics present severe limitations and side effects which impact patients' health and quality of life. For instance, although these drugs target mainly the dopamine system, they present target promiscuity and work by distinct mechanisms of action. As a consequence, complete comprehension of their pharmacological properties remains elusive. This chapter highlights research from the past 5 years that contributed to our current understanding of the mechanism of action and molecular features triggered by antipsychotic drugs in brain cells. In addition, we briefly discuss potential new therapeutic targets and strategies to treat schizophrenia.

Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern.

The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlovid® and the polymerase inhibitor molnupiravir, both targeting mutant-prone viral components, were approved for high-risk COVID-19 patients. Nevertheless, effective therapeutics to treat COVID-19 are urgently needed, especially small molecules acting independently of VoCs and targeting genetically stable cellular pathways which are crucial for viral replication. Pamapimod is a selective inhibitor of p38 Mitogen-Activated Protein Kinase alpha (p38 MAPKα) that has been extensively clinically evaluated for the treatment of rheumatoid arthritis. Signaling via p38 has recently been described as a key pathway for the replication of SARS-CoV-2. Here, we reveal that the combination of pamapimod with pioglitazone, an anti-inflammatory and approved drug for the treatment of type 2 diabetes, possesses potent and synergistic activity to inhibit SARS-CoV-2 replication in vitro. Both drugs showed similar antiviral potency across several cultured cell types and similar antiviral activity against SARS-CoV-2 Wuhan type, and the VoCs Alpha, Beta, Gamma, Delta, and Omicron. These data support the combination of pamapimod and pioglitazone as a potential therapy to reduce duration and severity of disease in COVID-19 patients, an assumption currently evaluated in an ongoing phase II clinical study.

Role of calcium ion channels and cytoskeletal proteins in Thorium-232 induced toxicity in normal human liver cells (WRL 68) and its validation in swiss mice.

Hepatic disorders reported in humans exposed to Thorium-232 (Th-232) rationalizes the present study investigating the toxicological response of normal human liver cells (WRL 68) and its validation in Swiss mice. Cell count analysis of WRL 68 cells-treated with Th-nitrate (1-200 µM) estimated IC50 of ∼24 µM (at 24 h) and 35 µM (at 48 h). Analysis of cell viability (trypan blue assay) showed the IC50 of ∼172 µM. Phase contrast bright-field microscopy revealed Th-induced morphological changes and cell-released microvesicle-like structures in extracellular space. Th-estimation by ICP-MS (Inductively-coupled plasma mass-spectrometry) showed uptake of Th by cells as a function of concentration and incubation time. Employing DTPA as a chelating agent in cell harvesting solution, cell-internalized/strongly-bound Th was estimated to be ∼42% of total incubated Th. Th-uptake studies in the presence of ion-channel specific inhibitors (e.g. nifedipine, thapsigargin) revealed the role of plasma membrane calcium channels and cytoplasmic calcium in modulating the Th-uptake. Transmission electron microscopy of Th-treated cells showed cell-derived extracellular vesicles, alterations in the shape and size of nucleus and mitochondria as well as cytoplasmic inclusions. The order of Th accumulation in various sub-cellular protein fractions was found to be as cytoskeleton (43%) > cytoplasmic (15%) > chromatin (7%) > nuclear (5%) & membrane (5%). Immunofluorescence analysis of WRL 68 cells showed that Th significantly altered the expression of cytoskeleton proteins (F-actin and keratin), which was further validated in liver tissues of Swiss mice administered with Th-232. Findings herein highlight the role of calcium channels and cytoskeleton in Th-induced toxicity. Keywords: Thorium toxicity; Liver cells; Calcium channels; Sub-cellular targets, Cytoskeleton; Swiss Mice.

Transcriptomics reveals the action mechanisms and cellular targets of citrate-coated silver nanoparticles in a ubiquitous aquatic fungus.

Silver nanoparticles (AgNPs) are among the major groups of contaminants of emerging concern for aquatic ecosystems. The massive application of AgNPs relies on the antimicrobial properties of Ag, raising concerns about their potential risk to ecologically important freshwater microbes and the processes they drive. Moreover, it is still uncertain whether the effects of AgNPs are driven by the same mechanisms underlying those of Ag ions (Ag+). We employed transcriptomics to better understand AgNP toxicity and disentangle the role of Ag+ in the overall toxicity towards aquatic fungi. To that end, the worldwide-distributed aquatic fungus Articulospora tetracladia, that plays a central role in organic matter turnover in freshwaters, was selected and exposed for 3 days to citrate-coated AgNPs (∼20 nm) and Ag+ at concentrations inhibiting 20% of growth (EC20). Responses revealed 258 up- and 162 down-regulated genes upon exposure to AgNPs and 448 up- and 84 down-regulated genes under exposure to Ag+. Different gene expression patterns were found after exposure to each silver form, suggesting distinct mechanisms of action. Gene ontology (GO) analyses showed that the major cellular targets likely affected by both silver forms were the biological membranes. GO-based biological processes indicated that AgNPs up-regulated the genes involved in transport, nucleobase metabolism and energy production, but down-regulated those associated with redox and carbohydrate metabolism. Ag+ up-regulated the genes involved in carbohydrate and steroid metabolism, whereas genes involved in localization and transport were down-regulated. Our results showed, for the first time, distinct profiles of gene expression in aquatic fungi exposed to AgNPs and Ag+, supporting different modes of toxicity of each silver form. Also, our results suggest that Ag+ had a negligible role in the toxicity induced by AgNPs. Finally, our study highlights the power of transcriptomics in portraying the stress induced by different silver forms in organisms.

Viral Vectors, Animal Models, and Cellular Targets for Gene Therapy of Cystic Fibrosis Lung Disease.

After more than two decades since clinical trials tested the first use of recombinant adeno-associated virus (rAAV) to treat cystic fibrosis (CF) lung disease, gene therapy for this disorder has undergone a tremendous resurgence. Fueling this enthusiasm has been an enhanced understanding of rAAV transduction biology and cellular processes that limit transduction of airway epithelia, the development of new rAAV serotypes and other vector systems with high-level tropism for airway epithelial cells, an improved understanding of CF lung pathogenesis and the cellular targets for gene therapy, and the development of new animal models that reproduce the human CF disease phenotype. These advances have created a preclinical path for both assessing the efficacy of gene therapies in the CF lung and interrogating the target cell types in the lung required for complementation of the CF disease state. Lessons learned from early gene therapy attempts with rAAV in the CF lung have guided thinking for the testing of next-generation vector systems. Although unknown questions still remain regarding the cellular targets in the lung that are required or sufficient to complement CF lung disease, the field is now well positioned to tackle these challenges. This review will highlight the role that next-generation CF animal models are playing in the preclinical development of gene therapies for CF lung disease and the knowledge gaps in disease pathophysiology that these models are attempting to fill.

ESC Working Group on Coronary Pathophysiology and Microcirculation position paper on 'coronary microvascular dysfunction in cardiovascular disease'.

Although myocardial ischaemia usually manifests as a consequence of atherosclerosis-dependent obstructive epicardial coronary artery disease, a significant percentage of patients suffer ischaemic events in the absence of epicardial coronary artery obstruction. Experimental and clinical evidence highlight the abnormalities of the coronary microcirculation as a main cause of myocardial ischaemia in patients with 'normal or near normal' coronary arteries on angiography. Coronary microvascular disturbances have been associated with early stages of atherosclerosis even prior to any angiographic evidence of epicardial coronary stenosis, as well as to other cardiac pathologies such as myocardial hypertrophy and heart failure. The main objectives of the manuscript are (i) to provide updated evidence in our current understanding of the pathophysiological consequences of microvascular dysfunction in the heart; (ii) to report on the current knowledge on the relevance of cardiovascular risk factors and comorbid conditions for microcirculatory dysfunction; and (iii) to evidence the relevance of the clinical consequences of microvascular dysfunction. Highlighting the clinical importance of coronary microvascular dysfunction will open the field for research and the development of novel strategies for intervention will encourage early detection of subclinical disease and will help in the stratification of cardiovascular risk in agreement with the new concept of precision medicine.

Exploring the Molecular Mechanisms Underlying the in†vitro Anticancer Effects of Multitarget-Directed Hydrazone Ruthenium(II)-Arene Complexes.

The molecular targets and the modes of action behind the cytotoxicity of two structurally established N,O- or N,N-hydrazone ruthenium(II)-arene complexes were explored in human breast adenocarcinoma cells (MCF-7) and paralleled in non-cancerous and cisplatin-resistant counterparts (MCF-10A and MCF-7CR respectively). Both complexes, [Ru(hmb)(L1)Cl] (1, L1=4-((2-(2,4-dinitrophenyl)hydrazono)(phenyl)methyl)-3-methyl-1-phenyl-1H-pyrazol-5-olate) and [Ru(cym)(L2)Cl] (2, L2=1-((3-methyl-5-oxo-1-phenyl-1H-pyrazol-4(5H)-ylidene)(phenyl)methyl)-2-(pyridin-2-yl)hydrazin-1-ide), reversibly interact with moderate-to-high affinity with a number of molecular targets in cell-free assays, namely serum albumin, DNA, the 20S proteasome and hydroxymethylglutaryl-CoA reductase. Most interestingly, only 2 readily crosses the cell membrane and preserves its binding/modulatory ability toward the targets of interest upon rapid cellular internalization. The resulting action at multiple levels of the cancer cascade is likely the cause for the selective sensitization of tumour cells to p27-mediated apoptotic death, and for the ability of 2 to overcome the drug resistance problem.

Antimicrobial Activity of, and Cellular Pathways Targeted by, p-Anisaldehyde and Epigallocatechin Gallate in the Opportunistic Human Pathogen Pseudomonas aeruginosa.

Plant-derived aldehydes are constituents of essential oils that possess broad-spectrum antimicrobial activity and kill microorganisms without promoting resistance. In our previous study, we incorporated p-anisaldehyde from star anise into a polymer network called proantimicrobial networks via degradable acetals (PANDAs) and used it as a novel drug delivery platform. PANDAs released p-anisaldehyde upon a change in pH and humidity and controlled the growth of the multidrug-resistant pathogen Pseudomonas aeruginosa PAO1. In this study, we identified the cellular pathways targeted by p-anisaldehyde by generating 10,000 transposon mutants of PAO1 and screened them for hypersensitivity to p-anisaldehyde. To improve the antimicrobial efficacy of p-anisaldehyde, we combined it with epigallocatechin gallate (EGCG), a polyphenol from green tea, and demonstrated that it acts synergistically with p-anisaldehyde in killing P. aeruginosa We then used transcriptome sequencing to profile the responses of P. aeruginosa to p-anisaldehyde, EGCG, and their combination. The exposure to p-anisaldehyde altered the expression of genes involved in modification of the cell envelope, membrane transport, drug efflux, energy metabolism, molybdenum cofactor biosynthesis, and the stress response. We also demonstrate that the addition of EGCG reversed many p-anisaldehyde-coping effects and induced oxidative stress. Our results provide insight into the antimicrobial activity of p-anisaldehyde and its interactions with EGCG and may aid in the rational identification of new synergistically acting combinations of plant metabolites. Our study also confirms the utility of the thiol-ene polymer platform for the sustained and effective delivery of hydrophobic and volatile antimicrobial compounds.IMPORTANCE Essential oils (EOs) are plant-derived products that have long been exploited for their antimicrobial activities in medicine, agriculture, and food preservation. EOs represent a promising alternative to conventional antibiotics due to their broad-range antimicrobial activity, low toxicity to human commensal bacteria, and capacity to kill microorganisms without promoting resistance. Despite the progress in the understanding of the biological activity of EOs, our understanding of many aspects of their mode of action remains inconclusive. The overarching aim of this work was to address these gaps by studying the molecular interactions between an antimicrobial plant aldehyde and the opportunistic human pathogen Pseudomonas aeruginosa The results of this study identify the microbial genes and associated pathways involved in the response to antimicrobial phytoaldehydes and provide insights into the molecular mechanisms governing the synergistic effects of individual constituents within essential oils.

The flowering hormone florigen accelerates secondary cell wall biogenesis to harmonize vascular maturation with reproductive development.

Florigen, a proteinaceous hormone, functions as a universal long-range promoter of flowering and concurrently as a generic growth-attenuating hormone across leaf and stem meristems. In flowering plants, the transition from the vegetative phase to the reproductive phase entails the orchestration of new growth coordinates and a global redistribution of resources, signals, and mechanical loads among organs. However, the ultimate cellular processes governing the adaptation of the shoot system to reproduction remain unknown. We hypothesized that if the mechanism for floral induction is universal, then the cellular metabolic mechanisms underlying the conditioning of the shoot system for reproduction would also be universal and may be best regulated by florigen itself. To understand the cellular basis for the vegetative functions of florigen, we explored the radial expansion of tomato stems. RNA-Seq and complementary genetic and histological studies revealed that florigen of endogenous, mobile, or induced origins accelerates the transcription network navigating secondary cell wall biogenesis as a unit, promoting vascular maturation and thereby adapting the shoot system to the developmental needs of the ensuing reproductive phase it had originally set into motion. We then demonstrated that a remarkably stable and broadly distributed florigen promotes MADS and MIF genes, which in turn regulate the rate of vascular maturation and radial expansion of stems irrespective of flowering or florigen level. The dual acceleration of flowering and vascular maturation by florigen provides a paradigm for coordinated regulation of independent global developmental programs.

CO-Releasing Materials: An Emphasis on Therapeutic Implications, as Release and Subsequent Cytotoxicity Are the Part of Therapy.

The CO-releasing materials (CORMats) are used as substances for producing CO molecules for therapeutic purposes. Carbon monoxide (CO) imparts toxic effects to biological organisms at higher concentration. If this characteristic is utilized in a controlled manner, it can act as a cell-signaling agent for important pathological and pharmacokinetic functions; hence offering many new applications and treatments. Recently, research on therapeutic applications using the CO treatment has gained much attention due to its nontoxic nature, and its injection into the human body using several conjugate systems. Mainly, there are two types of CO insertion techniques into the human body, i.e., direct and indirect CO insertion. Indirect CO insertion offers an advantage of avoiding toxicity as compared to direct CO insertion. For the indirect CO inhalation method, developers are facing certain problems, such as its inability to achieve the specific cellular targets and how to control the dosage of CO. To address these issues, researchers have adopted alternative strategies regarded as CO-releasing molecules (CORMs). CO is covalently attached with metal carbonyl complexes (MCCs), which generate various CORMs such as CORM-1, CORM-2, CORM-3, ALF492, CORM-A1 and ALF186. When these molecules are inserted into the human body, CO is released from these compounds at a controlled rate under certain conditions or/and triggers. Such reactions are helpful in achieving cellular level targets with a controlled release of the CO amount. However on the other hand, CORMs also produce a metal residue (termed as i-CORMs) upon degradation that can initiate harmful toxic activity inside the body. To improve the performance of the CO precursor with the restricted development of i-CORMs, several new CORMats have been developed such as micellization, peptide, vitamins, MOFs, polymerization, nanoparticles, protein, metallodendrimer, nanosheet and nanodiamond, etc. In this review article, we shall describe modern ways of CO administration; focusing primarily on exclusive features of CORM's tissue accumulations and their toxicities. This report also elaborates on the kinetic profile of the CO gas. The comprehension of developmental phases of CORMats shall be useful for exploring the ideal CO therapeutic drugs in the future of medical sciences.

Novel Therapeutics for Epstein⁻Barr Virus.

Epstein⁻Barr virus (EBV) is a human γ-herpesvirus that infects up to 95% of the adult population. Primary EBV infection usually occurs during childhood and is generally asymptomatic, though the virus can cause infectious mononucleosis in 35⁻50% of the cases when infection occurs later in life. EBV infects mainly B-cells and epithelial cells, establishing latency in resting memory B-cells and possibly also in epithelial cells. EBV is recognized as an oncogenic virus but in immunocompetent hosts, EBV reactivation is controlled by the immune response preventing transformation in vivo. Under immunosuppression, regardless of the cause, the immune system can lose control of EBV replication, which may result in the appearance of neoplasms. The primary malignancies related to EBV are B-cell lymphomas and nasopharyngeal carcinoma, which reflects the primary cell targets of viral infection in vivo. Although a number of antivirals were proven to inhibit EBV replication in vitro, they had limited success in the clinic and to date no antiviral drug has been approved for the treatment of EBV infections. We review here the antiviral drugs that have been evaluated in the clinic to treat EBV infections and discuss novel molecules with anti-EBV activity under investigation as well as new strategies to treat EBV-related diseases.

Advances in Zika Virus⁻Host Cell Interaction: Current Knowledge and Future Perspectives.

Emerging mosquito-transmitted RNA viruses, such as Zika virus (ZIKV) and Chikungunya represent human pathogens of an immense global health problem. In particular, ZIKV has emerged explosively since 2007 to cause a series of epidemics in the South Pacific and most recently in the Americas. Although typical ZIKV infections are asymptomatic, ZIKV infection during pregnancy is increasingly associated with microcephaly and other fetal developmental abnormalities. In the last few years, genomic and molecular investigations have established a remarkable progress on the pathogenic mechanisms of ZIKV infection using in vitro and in vivo models. Here, we highlight recent advances in ZIKV-host cell interaction studies, including cellular targets of ZIKV, ZIKV-mediated cell death mechanisms, host cell restriction factors that limit ZIKV replication, and immune evasion mechanisms utilized by ZIKV. Understanding of the mechanisms of ZIKV⁻host interaction at the cellular level will contribute crucial insights into the development of ZIKV therapeutics and vaccines.