Search Results (83)

Herpes simplex virus (HSV) is a prevalent and persistent human pathogen belonging to the family Herpesviridae and classified as an alpha-herpesvirus. It comprises two distinct types, HSV-1 and HSV-2, which together infect a significant portion of the global population and pose substantial public health challenges. HSV-1 is typically associated with oral herpes, while HSV-2 primarily causes genital herpes; both are characterized by recurrent lesions, latent infection, and mucocutaneous discomfort. Conventional antiviral drugs such as acyclovir and its derivatives are limited by drug resistance, potential toxicity, and their inability to eradicate latent viral reservoirs. These limitations have prompted increasing interest in alternative therapeutic strategies. Phenolic acids and tannins, plant-derived polyphenolic compounds, have attracted considerable attention due to their potent antiviral properties against various viruses, including HSV. This review summarizes current research on phenolic acids and tannins as promising natural antivirals against HSV, with a focus on their mechanisms of action and efficacy in disrupting multiple stages of the HSV life cycle. Full article

Dysregulated expression of nuclear receptor superfamily 4 group A member 2 (NR4A2) has recently been associated with autistic spectrum disorder (ASD), speech impairment, and neurodevelopmental delay (NDD); however, its precise role in the prevalence and etiopathogenesis of ASD has not been fully elucidated. Herein, we aimed to explore the role of NR4A2 variants in the genetic underpinnings of ASD among Saudi children of different age ranges and phenotype severities. A total of 338 children with ASD from 315 unrelated families (293 simplex, 2 quads, and 1 quintet) were screened for NR4A2 variants via exome sequencing (ES) of the genomic DNA extracted from peripheral blood mononuclear cells (PBMCs), after which the probands with identified NR4A2 variants were further subjected to trio genetic analyses. ES analysis revealed 10 de novo NR4A2 variants (5 indels/nonsense, 2 missense, and 3 variants affecting splicing) in 8 unrelated probands (2.37%) and 2 affected siblings from 8 unrelated families (6 simplex (2.04%) and 2 quads (8.7%)). Three NR4A2 variants were notably recurrent among both affected and unaffected carriers. All identified indels and two splicing variants met the criteria for pathogenic/loss-of-function (LoF) variants according to the ACMG classification (PVS1), whereas the missense variants were classified as of uncertain significance (VUS). This study is among the first to identify such a high frequency of recurrent variants in an ASD cohort, suggesting their significant contribution to the etiopathogenesis of ASD within this population. Full article

Duck plague (DP), caused by duck plague virus (DPV), is a highly contagious and fatal disease among waterfowl. UL3.5, an unconserved gene belonging to the Herpesviridae family, Alphaherpesvirinae subfamily, and Mardivirus genus, is located downstream of UL3 and exhibits high variability in size and sequence, with an absence in herpes simplex virus (HSV). Currently, there is little understanding of DPV UL3.5. In this study, we determined that DPV pUL3.5 is distributed within the cytoplasm and co-located with multiple organelles. In addition, we investigated the genetic type of DPV UL3.5 and found that it is an early gene encoding an early viral protein. To further explore the function of DPV UL3.5, we constructed DPV-BAC-δUL3.5 and discovered that the deletion of UL3.5 significantly impacts the viral secondary envelopment and release processes. Furthermore, the UL3.5-deleted virus shows defects in cell-to-cell spread. In conclusion, our findings demonstrate, for the first time, that the early viral protein encoded by DPV UL3.5 plays a crucial role in promoting viral replication. This offers fundamental insights for further investigations into the function of DPV UL3.5. Full article

Corneal endotheliitis is an inflammatory process, most commonly of viral etiology, that manifests clinically with features including corneal edema, keratic precipitates, and a mild anterior chamber reaction. Several studies have implicated human herpesviruses from the Herpesviridae family as primary causes of corneal endotheliitis, including cytomegalovirus (CMV), varicella zoster virus (VZV), and herpes simplex viruses 1 and 2 (HSV-1 and HSV-2). This review critically evaluates the present literature surrounding herpesvirus infections of the corneal endothelium. Full article

Repressor element-1 silencing transcription factor or neuron-restrictive silencer factor (REST/NRSF) is an extensively studied neuronal gene regulator both in neuronal cells and non-neuronal cells. Even though the role of REST in host cellular gene regulation is well established, its role in the establishment of viral infections and its capability to stabilize and destabilize such viral infections are scarcely studied. Co-repressor and DNA modifiers are involved in REST-mediated repressive action of its target genes. The role of REST and co-repressors together or individually in the regulation of viral as well as host genes has been unraveled in a few viruses such as HIV and influenza as well as two of the herpesvirus family members, namely herpes simplex virus type 1 (HSV-1) and Kaposi’s sarcoma-associated herpesvirus (KSHV). Here, we summarize all such virus studies involved with REST to gain a better insight into REST biology in virus infections. We also focus on unraveling the possible RE-1 binding sites in the Epstein–Barr virus (EBV) genome, a well-known human oncogenic herpesvirus that is associated with infectious mononucleosis and neoplasms such as B-cell lymphomas, nasopharyngeal carcinoma, gastric carcinoma, etc. An in silico-based approach was employed towards the prediction of such possible RE-1 binding elements in the EBV genome. This review advances the present knowledge of REST in virus infection which will aid in future efforts towards a better understanding of how REST acts in herpesviruses and other viruses for their infections and pathogenesis. Full article

The evergreen coniferous tree Thuja occidentalis is a member of the Cupressaceae family. This study included biological, cytotoxic, and in silico docking analyses in addition to a phytochemical composition analysis of the plant leaves and stem ethanolic extracts. The extracts’ in vitro cytotoxicity efficacy against various cancer cell lines was examined. Additionally, certain phytochemical compounds were identified by gas chromatographic analysis and subsequently assessed in silico against anticancer molecular targets. Also, their antiviral effect was assessed. Good cytotoxic activity was demonstrated by plant extracts against the lung and colorectal cancer cell lines. With half-maximal inhibitory concentration values of 18.45 μg/mL for the leaf extract and 33.61 μg/mL for the stem extract, apoptosis and S-phase arrest was observed in the lung cancer cell line. In addition, the leaf extract demonstrated effective antiviral activity, with suppression rates of 17.7 and 16.2% for the herpes simplex and influenza viruses, respectively. Gas chromatographic analysis revealed the presence of relevant bioactive components such as Podocarp-7-en-3β-ol, 13β-methyl-13-vinyl, Megastigmatrienone, and Cedrol, which were tested in silico against anticancer molecular targets. Our findings suggest that plant ethanolic extracts may have potential therapeutic uses as anticancer drugs against lung cancer in addition to their antiviral properties, which opens up further avenues for more investigation and applications. Full article

There are still several viral infections affecting a considerable number of the world’s population, causing thousands of deaths each year. There are no drugs available for most viral infections and for many not even a vaccine. The marine kingdom is characterized by a huge chemical diversity; however, there is currently on the market only one drug derived from the sea with antiviral properties, called Ara-A. In the current study, we used a solid phase extraction method (SPE) to obtain pre-purified fractions from Diacronema lutheri raw extracts. We tested both raw extracts and fractions against enveloped and non-enveloped viruses. Results showed an antiviral activity of fraction C of D. lutheri against the herpes simplex virus type 1 (HSV-1 strain SC16). Liquid chromatography coupled with untargeted high-resolution tandem mass spectrometry (LC-HRMS²) were employed to chart the metabolite distribution in all SPE fractions and pinpoint molecular families unique (or almost unique) to the bioactive fraction. Sulfoquinovosyl di- and monoacylglycerols (SQDGs and SQMGs) and di- and monogalactosyl monoacylglycerols (DGMGs and MGMGs) represent the largest groups of compounds in fraction C and they are likely responsible for the antiviral properties of this fraction. Full article

The composition of clay minerals in soils, and more particularly the presence of montmorillonite (as part of the smectite family), is a key factor in soil swell–shrinking as well as off–road vehicle mobility. Detecting these topsoil clay minerals and quantifying the montmorillonite abundance are a challenge since they are usually intimately mixed with other minerals, soil organic carbon and soil moisture content. Imaging spectroscopy coupled with unmixing methods can address these issues, but the quality of the estimation degrades the coarser the spatial resolution is due to pixel heterogeneity. With the advent of UAV-borne and proximal hyperspectral acquisitions, it is now possible to acquire images at a centimeter scale. Thus, the objective of this paper is to evaluate the accuracy and limitations of unmixing methods to retrieve montmorillonite abundance from very-high-resolution hyperspectral images (1.5 cm) acquired from a camera installed on top of a bucket truck over three different agricultural fields, in Loiret department, France. Two automatic endmember detection methods based on the assumption that materials are linearly mixed, namely the Simplex Identification via Split Augmented Lagrangian (SISAL) and the Minimum Volume Constrained Non-negative Matrix Factorization (MVC-NMF), were tested prior to unmixing. Then, two linear unmixing methods, the fully constrained least square method (FCLS) and the multiple endmember spectral mixture analysis (MESMA), and two nonlinear unmixing ones, the generalized bilinear method (GBM) and the multi-linear model (MLM), were performed on the images. In addition, several spectral preprocessings coupled with these unmixing methods were applied in order to improve the performances. Results showed that our selected automatic endmember detection methods were not suitable in this context. However, unmixing methods with endmembers taken from available spectral libraries performed successfully. The nonlinear method, MLM, without prior spectral preprocessing or with the application of the first Savitzky–Golay derivative, gave the best accuracies for montmorillonite abundance estimation using the USGS library (RMSE between 2.2–13.3% and 1.4–19.7%). Furthermore, a significant impact on the abundance estimations at this scale was in majority due to (i) the high variability of the soil composition, (ii) the soil roughness inducing large variations of the illumination conditions and multiple surface scatterings and (iii) multiple volume scatterings coming from the intimate mixture. Finally, these results offer a new opportunity for mapping expansive soils from imaging spectroscopy at very high spatial resolution. Full article

Proliferating cell nuclear antigen (PCNA) is a well-documented accessory protein of DNA repair and replication. It belongs to the sliding clamp family of proteins that encircle DNA and acts as a mobile docking platform for interacting proteins to mount and perform their metabolic tasks. PCNA presence is ubiquitous to all cells, and when located in the nucleus it plays a role in DNA replication and repair, cell cycle control and apoptosis in proliferating cells. It also plays a crucial role in the infectivity of some viruses, such as herpes simplex viruses (HSVs). However, more recently it has been found in the cytoplasm of immune cells such as neutrophils and macrophages where it has been shown to be involved in the development of a pro-inflammatory state. PCNA is also expressed on the surface of certain cancer cells and can play a role in preventing immune cells from killing tumours, as well as being associated with cancer virulence. Given the growing interest in oncolytic viruses (OVs) as a novel cancer therapeutic, this review considers the role of PCNA in healthy, cancerous, and immune cells to gain an understanding of how PCNA targeted therapy and oncolytic virotherapy may interact in the future. Full article

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome characterized by an uncontrolled hyperinflammatory reaction. HLH is classified into primary (familial) and secondary (acquired). Secondary HLH is commonly triggered by infections, with viral infections being a leading cause. Its epidemiology and clinical features in cases associated with herpes simplex virus 1 and 2 remain underexplored. This study aimed to review all previously described cases of HSV-1 or -2-triggered HLH and provide information about this syndrome’s epidemiology, microbiology, clinical characteristics, treatment, and outcomes. Methods: A narrative review was performed based on a search in PubMed, the Cochrane Library, and Scopus. Studies published until 27 April 2024 providing relevant data for HLH due to HSV 1 and 2 in humans were included. Results: We identified 29 eligible studies reporting HLH due to HSV 1 and 2, involving 34 patients. Half of them were adults, and half were neonates. Fever and splenomegaly were the most common clinical findings. Most patients were diagnosed with HSV-1 (64.7%), with PCR being the primary diagnostic method. The median duration of in-hospital treatment was 21 days, with acyclovir and steroids being the mainstays of therapy. The overall mortality rate was 41.2%, and AST levels emerged as an independent predictor of mortality. Conclusions: Our findings underscore the need for heightened awareness surrounding HLH triggered by HSV 1 and 2 and the importance of prompt diagnosis and tailored treatment approaches. Full article

Autophagy engulfs cellular components in double-membrane-bound autophagosomes for clearance and recycling after fusion with lysosomes. Thus, autophagy is a key process for maintaining proteostasis and a powerful cell-intrinsic host defense mechanism, protecting cells against pathogens by targeting them through a specific form of selective autophagy known as xenophagy. In this context, ubiquitination acts as a signal of recognition of the cargoes for autophagic receptors, which direct them towards autophagosomes for subsequent breakdown. Nevertheless, autophagy can carry out a dual role since numerous viruses including members of the Orthoherpesviridae family can either inhibit or exploit autophagy for its own benefit and to replicate within host cells. There is growing evidence that Herpes simplex virus type 1 (HSV-1), a highly prevalent human pathogen that infects epidermal keratinocytes and sensitive neurons, is capable of negatively modulating autophagy. Since the effects of HSV-1 infection on autophagic receptors have been poorly explored, this study aims to understand the consequences of HSV-1 productive infection on the levels of the major autophagic receptors involved in xenophagy, key proteins in the recruitment of intracellular pathogens into autophagosomes. We found that productive HSV-1 infection in human neuroglioma cells and keratinocytes causes a reduction in the total levels of Ub conjugates and decreases protein levels of autophagic receptors, including SQSTM1/p62, OPTN1, NBR1, and NDP52, a phenotype that is also accompanied by reduced levels of LC3-I and LC3-II, which interact directly with autophagic receptors. Mechanistically, we show these phenotypes are the result of xenophagy activation in the early stages of productive HSV-1 infection to limit virus replication, thereby reducing progeny HSV-1 yield. Additionally, we found that the removal of the tegument HSV-1 protein US11, a recognized viral factor that counteracts autophagy in host cells, enhances the clearance of autophagic receptors, with a significant reduction in the progeny HSV-1 yield. Moreover, the removal of US11 increases the ubiquitination of SQSTM1/p62, indicating that US11 slows down the autophagy turnover of autophagy receptors. Overall, our findings suggest that xenophagy is a potent host defense against HSV-1 replication and reveals the role of the autophagic receptors in the delivery of HSV-1 to clearance via xenophagy. Full article

Background/Objectives: Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity. This study’s objectives are to obtain updated epidemiological data that will help identify the specific types and subtypes of EB, determine the case distribution in Romania, and establish the incidence and prevalence of the condition. Methods: This population-based observational study included Romanian patients and collected data from 2012 to 2024. The following information was recorded: date of birth, status (deceased or alive), date of death (if applicable/available), sex, county, and city of residence, EB type and subtype if available, diagnosis (clinical and/or immunofluorescence mapping, transmission electron microscopy, genetic molecular analysis), affected genes, inheritance, and affected family members. Results: The study included a total of 152 patients. The point prevalence (the proportion of the population with a condition at a specific point in time) and the incidence of EB in Romania were 6.77 per million population and 24.23 per million live births, respectively. EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), Kindler EB (KEB), and not otherwise specified EB, as well as EB (NOS), were the main types of the condition identified in 21%, 3%, 63%, 2%, and 11% of the total cases. The point prevalence and incidence for the same time intervals were 1.58 and 5.28 in EBS, 0.10 and 1.76 in JEB, 4.72 and 12.34 in DEB, 0.16 and 0 in KEB, and 0.21 and 4.85 in EB (NOS). Conclusions: The study provides updated epidemiological data for Romania and underlines the necessity for accurate diagnosis, facilitated by access to genetic molecular testing and better reporting systems. Full article

Background: Remarkable differences exist in the outcome of systemic cancer therapies. Lymphomas and leukemias generally respond well to systemic chemotherapies, while solid cancers often fail. We engineered different human cancer cells lines to uniformly express a modified herpes simplex virus thymidine kinase TK.007 as a suicide gene when ganciclovir (GCV) is applied, thus in theory achieving a similar response in all cell lines. Methods: Fifteen different cell lines were engineered to express the TK.007 gene. XTT-cell proliferation assays were performed and the IC₅₀-values were calculated. Functional kinome profiling, mRNA sequencing, and bottom-up proteomics analysis with Ingenuity pathway analysis were performed. Results: GCV potency varied among cell lines, with lymphoma and leukemia cells showing higher susceptibility than solid cancer cells. Functional kinome profiling implies a contribution of the SRC family kinases and decreased overall kinase activity. mRNA sequencing highlighted alterations in the MAPK pathways and bottom-up proteomics showed differences in apoptotic and epithelial junction signaling proteins. Conclusions: The histogenetic origin of cells influenced the susceptibility of human malignant cells towards cytotoxic agents with leukemias and lymphomas being more sensitive than solid cancer cells. Full article

Background/Objectives: Patients with rheumatoid arthritis (RA) are prone to develop infections. Methods: Accordingly, 195 untreated early (e)RA patients and 398 healthy controls were selected from women in Tatarstan’s cohort to study infectious history in the anamnesis (four criteria) and in the previous year (16 criteria). Information about annual infections was collected face-to-face from year to year by a qualified rheumatologist/general practitioner and included the active use of information from medical records. Results: In the anamnesis, tuberculosis, and pneumonia, and in the previous year, respiratory tract infections, skin infections, and herpes simplex virus reactivation incidence were reported to be increased in eRA patients, as well as the event number and duration of acute and chronic tonsillitis. Moreover, more bacterial-suspected upper respiratory infections and urinary tract infections were retrieved in sporadic eRA patients as compared to familial eRA patients. An elevated immunization against CCP prevented respiratory tract infection in those with HSV exacerbation. Finally, associations were retrieved between infection (event number/delay) and RA indices: (i) chronic tonsillitis exacerbations with disease activity and health assessment (HAQ) in familial eRA; (ii) bacterial-suspected upper respiratory infections with the number of swollen and tender joints in sporadic eRA; and (iii) HSV exacerbation with inflammation in eRA patients with negative/low response against CCP. Here, we demonstrate the complex nature of the interplay of RA with specific infections. Conclusions: For the first time, differences in the patterns of annual trivial infections and their links with RA indices were found in cohorts of familial and sporadic cases of the disease. Additionally, for the first time, we identified a remarkable relationship between early RA and exacerbations of chronic tonsillitis, as well as tuberculosis in the patient’s history. Altogether, this study supports the existence of a complex interplay between infections and RA at onset driven by familial status and the presence of anti-CCP Ab at elevated levels. Full article

Herpes simplex virus (HSV) infections are highly widespread among humans, producing symptoms ranging from ulcerative lesions to severe diseases such as blindness and life-threatening encephalitis. At present, there are no vaccines available, and some existing antiviral treatments can be ineffective or lead to adverse effects. As a result, there is a need for new anti-HSV drugs. In this report, the in vitro anti-HSV effect of 9,9′-norharmane dimer (nHo-dimer), which belongs to the β-carboline (βC) alkaloid family, was evaluated. The dimer exhibited no virucidal properties and did not impede either the attachment or penetration steps of viral particles. The antiviral effect was only exerted under the constant presence of the dimer in the incubation media, and the mechanism of action was found to involve later events of virus infection. Analysis of fluorescence lifetime imaging data showed that the nHo-dimer internalized well into the cells when present in the extracellular incubation medium, with a preferential accumulation into perinuclear organelles including mitochondria. After washing the host cells with fresh medium free of nHo-dimer, the signal decreased, suggesting the partial release of the compound from the cells. This agrees with the observation that the antiviral effect is solely manifested when the alkaloid is consistently present in the incubation media. Full article