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14 pages, 15804 KiB  
Article
Herpes Simplex 2 Virus Depletes Cells of DEAD-Box Helicase 3 Protein by Packaging It into Virions
by Carmen Rita Piazza, Giulia Lottini, Paola Quaranta, Paola Perrera, Fabio Filippini, Michele Lai, Cristina Di Primio, Giulia Freer and Mauro Pistello
Viruses 2025, 17(8), 1124; https://doi.org/10.3390/v17081124 - 15 Aug 2025
Viewed by 304
Abstract
Human DEAD-box helicase 3 (DDX3) is a multifunctional RNA helicase implicated in mRNA unwinding and the regulation of gene expression. While DDX3 has been extensively studied in the context of RNA virus replication, its role in DNA virus replication remains less understood. In [...] Read more.
Human DEAD-box helicase 3 (DDX3) is a multifunctional RNA helicase implicated in mRNA unwinding and the regulation of gene expression. While DDX3 has been extensively studied in the context of RNA virus replication, its role in DNA virus replication remains less understood. In this study, we explore the involvement of DDX3 in the life cycle of Herpes Simplex Virus type 2 (HSV-2), a double-stranded DNA virus. Silencing of DDX3 expression with siRNA significantly impaired HSV-2 replication, indicating that DDX3 supports viral propagation. Unexpectedly, HSV-2 infection led to a marked reduction in cellular DDX3 protein levels during in vitro replication in human cells, particularly at 24 h post-infection, corresponding to the peak of viral production. Notably, this decrease was not accompanied by a reduction in DDX3 mRNA levels, nor was it prevented by proteasome inhibition, suggesting an alternative mechanism of DDX3 depletion. Further analysis revealed substantial amounts of DDX3 protein within HSV-2 virions, supporting the hypothesis that DDX3 is packaged into viral particles during replication. We propose that HSV-2 exploits host DDX3 by incorporating it into progeny virions to facilitate early stages of infection in newly infected cells. However, no evidence linking DDX3 to the assembly process of HSV-2 particles was found. These findings expand the known functional repertoire of DDX3 and highlight its potential as a host factor co-opted by DNA viruses, suggesting a broader relevance in antiviral strategies. Full article
(This article belongs to the Section Animal Viruses)
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14 pages, 2266 KiB  
Article
PCV2 Infection Upregulates SOCS3 Expression to Facilitate Viral Replication in PK-15 Cells
by Yiting Li, Hongmei Liu, Yi Wu, Xiaomei Zhang, Juan Geng, Xin Wu, Wengui Li, Zhenxing Zhang, Jianling Song, Yifang Zhang and Jun Chai
Viruses 2025, 17(8), 1081; https://doi.org/10.3390/v17081081 - 5 Aug 2025
Viewed by 353
Abstract
Porcine circovirus type 2 (PCV2) is a globally prevalent swine pathogen that induces immunosuppression, predisposing pigs to subclinical infections. In intensive farming systems, PCV2 persistently impairs growth performance and vaccine efficacy, leading to substantial economic losses in the swine industry. Emerging evidence suggests [...] Read more.
Porcine circovirus type 2 (PCV2) is a globally prevalent swine pathogen that induces immunosuppression, predisposing pigs to subclinical infections. In intensive farming systems, PCV2 persistently impairs growth performance and vaccine efficacy, leading to substantial economic losses in the swine industry. Emerging evidence suggests that certain viruses exploit Suppressor of Cytokine Signaling 3 (SOCS3), a key immune checkpoint protein, to subvert host innate immunity by suppressing cytokine signaling. While SOCS3 has been implicated in various viral infections, its regulatory role in PCV2 replication remains undefined. This study aims to elucidate the mechanisms underlying the interplay between SOCS3 and PCV2 during viral pathogenesis. Porcine SOCS3 was amplified using RT-PCR and stably overexpressed in PK-15 cells through lentiviral delivery. Bioinformatics analysis facilitated the design of three siRNA candidates targeting SOCS3. We systematically investigated the effects of SOCS3 overexpression and knockdown on PCV2 replication kinetics and host antiviral responses by quantifying the viral DNA load and the mRNA levels of cytokines. PCV2 infection upregulated SOCS3 expression at both transcriptional and translational levels in PK-15 cells. Functional studies revealed that SOCS3 overexpression markedly enhanced viral replication, whereas its knockdown suppressed viral proliferation. Intriguingly, SOCS3-mediated immune modulation exhibited a divergent regulation of antiviral cytokines: PCV2-infected SOCS3-overexpressing cells showed elevated IFN-β but suppressed TNF-α expressions, whereas SOCS3 silencing conversely downregulated IFN-β while amplifying TNF-α responses. This study unveils a dual role of SOCS3 during subclinical porcine circovirus type 2 (PCV2) infection: it functions as a host-derived pro-viral factor that facilitates viral replication while simultaneously reshaping the cytokine milieu to suppress overt inflammatory responses. These findings provide novel insights into the mechanisms underlying PCV2 immune evasion and persistence and establish a theoretical framework for the development of host-targeted control strategies. Although our results identify SOCS3 as a key host determinant of PCV2 persistence, the precise molecular pathways involved require rigorous experimental validation. Full article
(This article belongs to the Section Animal Viruses)
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16 pages, 2608 KiB  
Article
Small Interfering RNAs Targeting VP4, VP3, 2B, or 3A Coding Regions of Enterovirus A71 Inhibit Viral Replication In Vitro
by Yun Ji Ga, Yun Young Go and Jung-Yong Yeh
Biomedicines 2025, 13(7), 1760; https://doi.org/10.3390/biomedicines13071760 - 18 Jul 2025
Viewed by 439
Abstract
Background: Enterovirus A71 (EV-A71) is considered as the primary causative agent of hand, foot, and mouth disease (HFMD) in young children, leading to severe neurological complications and contributing to substantial mortalities in recent HFMD outbreaks across Asia. Despite this, there is currently [...] Read more.
Background: Enterovirus A71 (EV-A71) is considered as the primary causative agent of hand, foot, and mouth disease (HFMD) in young children, leading to severe neurological complications and contributing to substantial mortalities in recent HFMD outbreaks across Asia. Despite this, there is currently no effective antiviral treatment available for EV-A71. RNA interference (RNAi) is a powerful mechanism of post-transcriptional gene regulation that utilizes small interfering RNA (siRNA) to target and degrade specific RNA sequences. Objectives: The aim of this study was to design various siRNAs targeting EV-A71 genomic regions and evaluate the RNAi efficacy against a novel, previously genetically uncharacterized EV-A71 strain. Methods: A novel EV-A71 strain was first sequenced to design target-specific siRNAs. The viral titers, viral protein expression, cytopathic effects, and cell viability of EV-A71-infected HeLa cells were examined to evaluate the specific viral inhibition by the siRNAs. Results: A substantial reduction in viral titers and viral protein synthesis was observed in EV-A71-infected HeLa cells treated with specific siRNAs targeting the VP4, VP3, 2B, and 3A genes. siRNAs delayed cytopathic effects and increased cell viability of EV-A71-infected HeLa cells. Nonspecific interferon induction caused by siRNAs was not observed in this study. In contrast, replication of coxsackievirus B3, another important member of the Enterovirus genus, remained unaffected. Conclusions: Overall, the findings demonstrate that RNAi targeting genomic regions of EV-A71 VP4, VP3, 2B, or 3A could become a potential strategy for controlling EV-A71 infection, and this promising result can be integrated into future anti-EV-A71 therapy developments. Full article
(This article belongs to the Special Issue Encephalitis and Viral Infection: Mechanisms and Therapies)
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22 pages, 1595 KiB  
Review
Therapeutic Approaches of Viral Gene Silencing by Small Interfering RNA: Strategies to Prevent the Emergence of Antiviral Resistant Escape Mutants
by Hara Kang, Yun Ji Ga, Jung Won Kim, Chaeyeon Kim, Se-Hwan Son, Chaeeun Gwak and Jung-Yong Yeh
Pharmaceuticals 2025, 18(7), 987; https://doi.org/10.3390/ph18070987 - 1 Jul 2025
Viewed by 647
Abstract
RNA interference (RNAi) was originally regarded as a mechanism of eukaryotic post-transcriptional gene regulation mediated by small interfering RNA (siRNA)-induced sequence-specific RNA degradation. It is well known to exert as an important antiviral defense mechanism in a wide range of organisms, from plants [...] Read more.
RNA interference (RNAi) was originally regarded as a mechanism of eukaryotic post-transcriptional gene regulation mediated by small interfering RNA (siRNA)-induced sequence-specific RNA degradation. It is well known to exert as an important antiviral defense mechanism in a wide range of organisms, from plants to invertebrates. The specificity, ease of design, and ability to target conserved gene regions make siRNA technology a promising approach to combat viral pathogenesis, allowing the targeting of multiple virus strains. The mechanism of sequence complementarity utilized by siRNAs against their targets presents a novel strategy to combat viral infections, as they can specifically target and degrade viral RNA. Consequently, siRNA-based therapeutics have been applied to various viral diseases. This is largely due to the design flexibility and rapid response potential of RNAi technologies, which provide advantages over traditional antiviral agents. However, the emergence of viral escape mutants poses a major barrier to the sustained antiviral activity of siRNA-based therapy. Therefore, devising strategies to overcome the emergence of escape mutants to antiviral siRNAs could enhance the efficacy of siRNA-based therapeutics in providing a rapid response to emerging viral infectious diseases. This review aims to comprehensively summarize the current knowledge on siRNA-based therapeutic approaches against viral infections and elucidate the challenges associated with implementing siRNA treatment, with a specific emphasis on antiviral resistance. Full article
(This article belongs to the Special Issue Design, Synthesis and Development of Novel Antiviral Agents)
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21 pages, 3195 KiB  
Article
Carrageenans and the Carrageenan-Echinochrome Complex as Anti-SARS-CoV-2 Agents
by Natalya V. Krylova, Anna O. Kravchenko, Galina N. Likhatskaya, Olga V. Iunikhina, Valery P. Glazunov, Tatyana S. Zaporozhets, Mikhail Y. Shchelkanov and Irina M. Yermak
Int. J. Mol. Sci. 2025, 26(13), 6175; https://doi.org/10.3390/ijms26136175 - 26 Jun 2025
Viewed by 404
Abstract
The diversity of structural types of carrageenans (CRGs)—sulfated polysaccharides of red algae—determines their different biological activities. The different types of CRGs (kappa, lambda, kappa/beta-CRGs) were isolated from the red algae of the Pacific coast. Molecular docking was performed to determine potential interactions of [...] Read more.
The diversity of structural types of carrageenans (CRGs)—sulfated polysaccharides of red algae—determines their different biological activities. The different types of CRGs (kappa, lambda, kappa/beta-CRGs) were isolated from the red algae of the Pacific coast. Molecular docking was performed to determine potential interactions of CRGs with the receptor-binding domain (RBD) of SARS-CoV-2 and its cellular receptor—angiotensin—converting enzyme type 2 (ACE2). CRGs interacted with ACE2 and RBD via hydrogen bonding and ionic interactions. The strongest binding affinity of CRGs and ACE2 was observed for kappa-CRG. Molecular docking was confirmed by results studying the effects of CRGs against SARS-CoV-2 in vitro. The ability of CRGs, as well as the complex CRG with sea urchin echinochrome (Ech), to inhibit SARS-CoV-2 replication in Vero E6 cells was studied using cytopathic effect (CPE) inhibition and RT-PCR assays. The simultaneous treatment of cells with CRGs and the virus revealed that kappa-CRG exhibited the most significant antiviral effect among all the polysaccharides, with a selective index (SI) of 33. The kappa-CRG/Ech complex exhibited the highest virucidal effect on SARS-CoV-2 particles with an SI above 70 (more than two times higher than that of CRG and Ech) and reduced viral RNA levels by 45% (IC = 45%). Our results illustrate that CRGs and kappa-CRG/Ech complex can act as protective agents against SARS-CoV-2. Full article
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21 pages, 5739 KiB  
Article
Novel Lung Cell-Penetrating Peptide Targets Alveolar Epithelial Type II Cells, Basal Cells, and Ionocytes
by Jin Wen, Gajalakshmi Singuru, Jeffrey Stiltner, Sanjay Mishra, Kyle S. Feldman, Kayla McCandless, Raymond Yurko, Kazi Islam, Ray Frizzell, Hisato Yagi, Jonathan M. Brown and Maliha Zahid
Pharmaceutics 2025, 17(7), 824; https://doi.org/10.3390/pharmaceutics17070824 - 25 Jun 2025
Viewed by 691
Abstract
Background: Cell-penetrating peptides cross cell membrane barriers while carrying cargoes in a functional form. Our work identified two novel lung-targeting peptides, S7A and R11A. Here, we present studies on biodistribution, the cell types targeted, and an in vitro proof of application. Methods: Studies [...] Read more.
Background: Cell-penetrating peptides cross cell membrane barriers while carrying cargoes in a functional form. Our work identified two novel lung-targeting peptides, S7A and R11A. Here, we present studies on biodistribution, the cell types targeted, and an in vitro proof of application. Methods: Studies were performed in human bronchial epithelial cells (HBECs) with and without various endocytic inhibitors, and coincubation with fluorescently labeled transferrin or endocytic markers. Cyclic R11A (cR11A) was conjugated to siRNA duplexes and anti-viral activity against SARS-CoV-2 was tested. Biodistribution studies were performed by injecting wild-type mice with fluorescently labeled peptides, and various circulation times were allowed for, as well as cross-staining of lung sections or isolated single cells with various cellular markers, followed by fluorescence-activated cell sorting or confocal microscopy. Results: cR11A showed peak uptake in 15 min, with the highest uptake in airway epithelial type II (ATII) cells, followed by p63+ basal cells and ionocytes. Cyclization increased transduction efficiencies ~100-fold. Endocytosis studies showed a decrease in peptide uptake by pre-treatment with Pitstop2 but not Amiloride or Nystatin. Endocytic marker Lamp1 showed colocalization at the earliest time point, with the escape of the peptide from endocytic vesicles later. cR11A conjugated to ant-spike and anti-envelop proteins showed anti-viral effects with an EC90 of 0.6 μM and 1.0 µM, respectively. Conclusions: We have identified a novel peptide, cR11A, that targets ATII, basal cells, and ionocytes, the cyclization of which increased transduction efficiency in vitro and in vivo. The uptake mechanism appears to be via clathrin-mediated endocytosis with escape from endocytic vesicles. cR11A can act as a vector to deliver anti-viral siRNA to epithelial cells. Full article
(This article belongs to the Section Biologics and Biosimilars)
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27 pages, 3506 KiB  
Article
The Involvement of LvSRSF2 in Circular RNA Biogenesis and Its Role in Immunity Against White Spot Syndrome Virus (WSSV) in Litopenaeus vannamei
by Wutthipat Potiyanadech, Cheeranan Sriphuttha, Tuangrak Seabkongseng, Neung Teaumroong, Panlada Tittabutr and Pakpoom Boonchuen
Int. J. Mol. Sci. 2025, 26(13), 5981; https://doi.org/10.3390/ijms26135981 - 21 Jun 2025
Viewed by 522
Abstract
Serine/arginine splicing factors (SRSFs) are critical regulators of gene expression that influence alternative splicing through RNA binding via the RNA recognition motif (RRM). Circular RNAs (circRNAs) are a subset of non-coding RNAs that exhibit differential expression in WSSV-infected Litopenaeus vannamei. This study [...] Read more.
Serine/arginine splicing factors (SRSFs) are critical regulators of gene expression that influence alternative splicing through RNA binding via the RNA recognition motif (RRM). Circular RNAs (circRNAs) are a subset of non-coding RNAs that exhibit differential expression in WSSV-infected Litopenaeus vannamei. This study investigates the role of LvSRSF2 in regulating circRNA expression in response to WSSV infection. LvSRSF2 was highly expressed in hemocytes and upregulated during WSSV infection. Silencing LvSRSF2 using dsRNA significantly upregulated the expression of circRNAs (circ-Alpha2, circ-Anillin, circ-Hemocytin, circ-Nephrin, and circ-Toll) in both WSSV-infected and uninfected shrimps at 72 h post-injection with dsRNAs. Knockdown of LvSRSF2 also significantly reduced WSSV copy numbers at 24 h post-infection and extended shrimp survival, with knockdown shrimp surviving up to 9 d compared to the control group. In addition, circ-Hemocytin, an SRSF2-related circRNA, was predicted to interact with six miRNAs targeting immune-related genes such as Toll, STAT, NF-κB, and Vago4. Following WSSV infection, circ-Hemocytin expression increased at 24 and 48 hpi, and the immune genes STAT and Vago4 were also upregulated, suggesting a potential circRNA–miRNA–mRNA regulatory axis in shrimp antiviral defense. Furthermore, targeted suppression of circ-Hemocytin expression using siRNAs significantly reduced its expression without affecting the corresponding linear transcript and resulted in a notable decrease in WSSV load in shrimp gills, highlighting its potential role in antiviral defense. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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24 pages, 1795 KiB  
Review
SARS-CoV-2 Replication Revisited: Molecular Insights and Current and Emerging Antiviral Strategies
by Bryan John J. Subong and Imelda L. Forteza
COVID 2025, 5(6), 85; https://doi.org/10.3390/covid5060085 - 30 May 2025
Viewed by 1279
Abstract
The replication machinery of SARS-CoV-2 is a primary target for therapeutic intervention, and has led to significant progress in antiviral medication discovery. This review consolidates contemporary molecular insights into viral replication and rigorously assesses treatment methods at different phases of viruses’ clinical development. [...] Read more.
The replication machinery of SARS-CoV-2 is a primary target for therapeutic intervention, and has led to significant progress in antiviral medication discovery. This review consolidates contemporary molecular insights into viral replication and rigorously assesses treatment methods at different phases of viruses’ clinical development. Direct-acting antivirals, such as nucleoside analogs (e.g., remdesivir, molnupiravir) and protease inhibitors (e.g., nirmatrelvir), have shown clinical effectiveness in diminishing morbidity and hospitalization rates. Simultaneously, host-targeted medicines like baricitinib, camostat, and brequinar leverage critical host–virus interactions, providing additional pathways to reduce viral replication while possibly minimizing the development of resistance. Notwithstanding these advancements, constraints in distribution methods, antiviral longevity, and the risk of mutational evasion demand novel strategies. Promising investigational approaches encompass CRISPR-mediated RNA degradation systems, inhalable siRNA-nanoparticle conjugates, and molecular glue degraders that target host and viral proteins. Furthermore, next-generation treatments aimed at underutilized enzyme domains (e.g., NiRAN, ExoN) and host chaperone systems (e.g., TRiC complex) signify a transformative approach in antiviral targeting. The integration of high-throughput phenotypic screening, AI-driven medication repurposing, and systems virology is transforming the antiviral discovery field. An ongoing interdisciplinary endeavor is necessary to convert these findings into versatile, resistance-resistant antiviral strategies that are applicable beyond the present pandemic and in future coronavirus epidemics. Full article
(This article belongs to the Special Issue New Antivirals against Coronaviruses)
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15 pages, 6104 KiB  
Article
Development of a Noninfectious Japanese Encephalitis Virus Replicon for Antiviral Drug Screening and Gene Function Studies
by Yang Yang, Jiayang Zheng, Yafang Lin, Yan Zhang, Qianming Zhao, Hailong Zhang, Junjie Zhang, Zongjie Li, Ke Liu, Beibei Li, Donghua Shao, Yafeng Qiu, Zhiyong Ma and Jianchao Wei
Viruses 2025, 17(6), 759; https://doi.org/10.3390/v17060759 - 27 May 2025
Viewed by 566
Abstract
Viral replicons are efficient tools to understand the mechanisms of viral replication and screen antiviral drugs. In this study, a viral-cDNA-based replicon of Japanese encephalitis virus (JEV), which is the causative agent of Japanese encephalitis, was constructed by replacing the viral structural proteins [...] Read more.
Viral replicons are efficient tools to understand the mechanisms of viral replication and screen antiviral drugs. In this study, a viral-cDNA-based replicon of Japanese encephalitis virus (JEV), which is the causative agent of Japanese encephalitis, was constructed by replacing the viral structural proteins with a green fluorescent protein (JEV-GFP replicon). The resulting JEV-GFP replicon was used as a tool to screen antiviral drugs targeting JEV nonstructural proteins, and the five compounds JNJ-A07, HZ-1157, NITD-2, quinine, and NITD008 were obtained, which significantly inhibited the replication of the JEV-GFP replicon and JEV in vitro, and the properties of these five compounds were also analyzed. The CC50, EC50, and SI indices of these five compounds were analyzed. In addition, the JEV-GFP replicon was used as a tool to identify the residues of viral nonstructural proteins involved in RNA replication, and the cysteine residue at position 4 of nonstructural protein 1 was found to be essential for JEV RNA replication. These data suggested that the noninfectious JEV-GFP replicon could be used as tool for different purposes, such as antiviral drug screening and gene function studies. Full article
(This article belongs to the Section Animal Viruses)
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18 pages, 5844 KiB  
Article
Construction of Minigenome Replicon of Nipah Virus and Investigation of Biological Activity
by Fan Wang, Ruyi Chen, Jiayi Zhong, Anqi Zhou, Ran Peng, Bao Xue, Yuan Zhou, Jielin Tang, Xinwen Chen and Qi Yang
Viruses 2025, 17(5), 707; https://doi.org/10.3390/v17050707 - 15 May 2025
Viewed by 984
Abstract
Nipah virus (NiV), a highly lethal zoonotic pathogen causing encephalitis and respiratory diseases with mortality rates up to 40–70%, faces research limitations due to its strict biosafety level 4 (BSL-4) containment requirements, hindering antiviral development. To address this, we generated two NiV minigenome [...] Read more.
Nipah virus (NiV), a highly lethal zoonotic pathogen causing encephalitis and respiratory diseases with mortality rates up to 40–70%, faces research limitations due to its strict biosafety level 4 (BSL-4) containment requirements, hindering antiviral development. To address this, we generated two NiV minigenome replicons (Fluc- and EGFP-based) expressed via helper plasmids encoding viral N, P, and L proteins, enabling replication studies under BSL-2 conditions. The minigenome replicon recapitulated the cytoplasmic inclusion body (IB) formation observed in live NiV infections. We further demonstrated that IB assembly is driven by liquid–liquid phase separation (LLPS), with biochemical analyses identifying the C-terminal N core domain of the N protein, as well as N0 and XD domains and the intrinsically disordered region (IDR) of the P protein, as essential structural determinants for LLPS-mediated IB biogenesis. The targeted siRNA silencing of the 5′ and 3′ untranslated regions (UTRs) significantly reduced replicon-derived mRNA levels, validating the regulatory roles of these regions. Importantly, the minigenome replicon demonstrated sensitivity to type I/II/III interferons and antivirals (remdesivir, azvudine, molnupiravir), establishing its utility for drug screening. This study provides a safe and efficient platform for investigating NiV replication mechanisms and accelerating therapeutic development, circumventing the constraints of BSL-4 facilities while preserving key virological features. Full article
(This article belongs to the Section Animal Viruses)
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24 pages, 7713 KiB  
Article
Resveratrol’s Pro-Apoptotic Effects in Cancer Are Mediated Through the Interaction and Oligomerization of the Mitochondrial VDAC1
by Tal Raviv, Anna Shteinfer-Kuzmine, Meital M. Moyal and Varda Shoshan-Barmatz
Int. J. Mol. Sci. 2025, 26(9), 3963; https://doi.org/10.3390/ijms26093963 - 22 Apr 2025
Viewed by 1053
Abstract
Resveratrol is a naturally occurring phenolic compound found in various foods such as red wine, chocolate, peanuts, and blueberries. Both in-vitro and in-vivo studies have shown that it has a broad spectrum of pharmacological effects such as providing cellular protection and promoting longevity. [...] Read more.
Resveratrol is a naturally occurring phenolic compound found in various foods such as red wine, chocolate, peanuts, and blueberries. Both in-vitro and in-vivo studies have shown that it has a broad spectrum of pharmacological effects such as providing cellular protection and promoting longevity. These effects include antioxidant, anti-inflammatory, neuroprotective, and anti-viral properties, as well as improvements in cardio-metabolic health and anti-aging benefits. Additionally, resveratrol has demonstrated the ability to induce cell death and inhibit tumor growth across different types and stages of cancer. However, the dual effects of resveratrol—acting to support cell survival in some contexts, while inducing cell death in others—is still not fully understood. In this study, we identify a novel target for resveratrol: the voltage-dependent anion channel 1 (VDAC1), a multi-functional outer mitochondrial membrane protein that plays a key role in regulating both cell survival and death. Our findings show that resveratrol increased VDAC1 expression levels and promoted its oligomerization, leading to apoptotic cell death. Additionally, resveratrol elevated intracellular Ca2+ levels and enhanced the production of reactive oxygen species (ROS). Resveratrol also induced the detachment of hexokinase I from VDAC1, a key enzyme in metabolism, and regulating apoptosis. When VDAC1 expression was silenced using specific siRNA, resveratrol-induced cell death was significantly reduced, indicating that VDAC1 is essential for its pro-apoptotic effects. Additionally, both resveratrol and its analog, trans-2,3,5,4′-tetrahydroxystilbene-2-O-glucoside (TSG), directly interacted with purified VDAC1, as revealed by microscale thermophoresis, with similar binding affinities. However, unlike resveratrol, TSG did not induce VDAC1 overexpression or apoptosis. These results demonstrate that resveratrol-induced apoptosis is linked to increased VDAC1 expression and its oligomerization. This positions resveratrol not only as a protective agent, but also as a pro-apoptotic compound. Consequently, resveratrol offers a promising therapeutic approach for cancer, with potentially fewer side effects compared to conventional treatments, due to its natural origins in plants and food products. Full article
(This article belongs to the Collection Feature Papers in Molecular Oncology)
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22 pages, 5674 KiB  
Article
Berberine Suppresses Influenza A Virus-Triggered Pyroptosis in Macrophages via Intervening in the mtROS-MAVS-NLRP3 Inflammasome Pathway
by Mengfan Zhao, Di Deng, Hui Liu, Rui Guo, Jun Wu, Yu Hao and Mingrui Yang
Viruses 2025, 17(4), 539; https://doi.org/10.3390/v17040539 - 7 Apr 2025
Cited by 1 | Viewed by 679
Abstract
Infection with influenza A virus (IAV) may trigger excessive inflammatory responses, leading to severe viral pneumonia and accelerating disease progression. Therefore, controlling these excessive inflammatory responses is crucial for the prevention and treatment of pneumonia caused by IAV. Berberine (BBR), an isoquinoline alkaloid [...] Read more.
Infection with influenza A virus (IAV) may trigger excessive inflammatory responses, leading to severe viral pneumonia and accelerating disease progression. Therefore, controlling these excessive inflammatory responses is crucial for the prevention and treatment of pneumonia caused by IAV. Berberine (BBR), an isoquinoline alkaloid extracted from traditional Chinese medicine, possesses extensive pharmacological activities. However, its immunoregulatory effects and molecular mechanisms in the context of IAV infection require further investigation. This study explored the impact of BBR on macrophage pyroptosis and inflammatory responses induced by IAV infection. Our findings revealed that BBR effectively inhibits the release of IL-1β and TNF-α induced by IAV infection and suppresses gasdermin D (GSDMD)-mediated pyroptosis in a dose-dependent manner. Further research indicates that BBR alleviates macrophage pyroptosis and inflammatory responses in IAV-infected cells by reducing the release of mitochondrial reactive oxygen species (mtROS), inhibiting mitochondrial antiviral signaling protein (MAVS) expression and blocking the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Experiments using siRNA to knockdown MAVS further confirmed the pivotal role of MAVS in BBR’s inhibition of IAV-induced macrophage pyroptosis. This study provides a scientific basis for the application of BBR as an anti-inflammatory drug in the treatment of inflammatory diseases caused by IAV infection and directs future research endeavors. Full article
(This article belongs to the Special Issue Roles of Macrophages in Viral Infections, 2nd Edition)
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25 pages, 1311 KiB  
Review
Emerging Strategies and Progress in the Medical Management of Marburg Virus Disease
by Sanctus Musafiri, Emmanuel Edwar Siddig, John Baptist Nkuranga, Athanase Rukundo, Tharcisse Mpunga, Augustin Sendegeya, Theogene Twagirumugabe, Ayman Ahmed and Claude Mambo Muvunyi
Pathogens 2025, 14(4), 322; https://doi.org/10.3390/pathogens14040322 - 27 Mar 2025
Cited by 1 | Viewed by 1533
Abstract
During the current outbreak of Marburg virus disease (MVD) in Rwanda, we synthesized evidence from the literature to improve case management. Accordingly, experimental treatment was offered to patients under close follow-up. Remdesivir alone or in combination with monoclonal antibody treatment (MBP091) complemented with [...] Read more.
During the current outbreak of Marburg virus disease (MVD) in Rwanda, we synthesized evidence from the literature to improve case management. Accordingly, experimental treatment was offered to patients under close follow-up. Remdesivir alone or in combination with monoclonal antibody treatment (MBP091) complemented with supportive care has improved the clinical outcomes of patients. Additionally, we have identified several experimental therapies currently under investigation, including antiviral drugs such as favipiravir, galidesivir, obeldesivir, and remdesivir, along with monoclonal and polyclonal antibodies (e.g., polyclonal IgG, monoclonal antibody MR-78-N; MR82-N; MR191-N; monoclonal antibodies MR186-YTE and MBP091). Furthermore, substantial progress is being made in vaccine development, with promising candidates including adenovirus-vectored vaccines, DNA vaccines, and the recombinant vesicular stomatitis virus (rVSV) vaccine. Moreover, innovative preventive and treatment strategies—such as synthetic hormones like estradiol benzoate, small interfering RNA (siRNA), interferon-β therapy, and phosphorodiamidate morpholino oligomers—are emerging as potential options for MVD management. Further investment is needed to accelerate research and optimize these therapeutics and preventive modalities. Additional epidemiological, preclinical, and clinical studies are warranted to generate the evidence required to inform policymaking, resource mobilization, and the implementation of cost-effective interventions for the prevention, control, and treatment of MVD. Full article
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14 pages, 3947 KiB  
Article
The Deubiquitinase OTUD1 Influences HIV-1 Release by Regulating the Host Restriction Factor BST-2
by Man-Di Zhang, Fan Chen, Wen-Qiang He, Ying Lu, Feng-Liang Liu, Hong-Guang Zhang, Liu-Meng Yang, Chun-Sheng Dong, Si-Dong Xiong and Yong-Tang Zheng
Viruses 2025, 17(2), 260; https://doi.org/10.3390/v17020260 - 14 Feb 2025
Cited by 1 | Viewed by 1003
Abstract
Bone marrow stromal cell antigen 2 (BST-2) is a restriction factor for human immunodeficiency virus type I (HIV-1) and plays an important role in regulating the release of viral particles. However, the antiviral efficacy of BST-2 is antagonized by the HIV-1-encoded accessory protein [...] Read more.
Bone marrow stromal cell antigen 2 (BST-2) is a restriction factor for human immunodeficiency virus type I (HIV-1) and plays an important role in regulating the release of viral particles. However, the antiviral efficacy of BST-2 is antagonized by the HIV-1-encoded accessory protein Vpu, which facilitates the degradation of BST-2 by recruiting E3 ubiquitin ligase β-TrCP. The involvement of deubiquitinases (DUBs) in counteracting BST-2 ubiquitination and influencing its stability during HIV-1 infection remains inadequately explored. In this study, we conducted a small interfering RNA (siRNA) screening of human DUBs and determined that OTUD1 interacts with BST-2, leading to a reduction in its K48- and K63-linked ubiquitination. This reduction increases BST-2 protein stability, and subsequently inhibits HIV-1 release. Our findings reveal a novel regulatory mechanism by which DUBs influence the stability of the HIV-1 restriction factor BST-2 to dampen viral release, providing a potential therapeutic target for HIV-1 antiviral intervention. Full article
(This article belongs to the Special Issue Cellular Mechanisms Regulating HIV Replication)
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32 pages, 7557 KiB  
Review
Potential Broad-Spectrum Antiviral Agents: A Key Arsenal Against Newly Emerging and Reemerging Respiratory RNA Viruses
by Quynh Xuan Thi Luong, Phuong Thi Hoang, Phuong Thi Ho, Ramadhani Qurrota Ayun, Taek Kyun Lee and Sukchan Lee
Int. J. Mol. Sci. 2025, 26(4), 1481; https://doi.org/10.3390/ijms26041481 - 10 Feb 2025
Cited by 7 | Viewed by 3540
Abstract
Respiratory viral infections present significant global health challenges, causing substantial morbidity and mortality, particularly among highly susceptible components of the population. The emergence of pandemics and epidemics, such as those caused by influenza viruses and coronaviruses, emphasizes the urgent need for effective antiviral [...] Read more.
Respiratory viral infections present significant global health challenges, causing substantial morbidity and mortality, particularly among highly susceptible components of the population. The emergence of pandemics and epidemics, such as those caused by influenza viruses and coronaviruses, emphasizes the urgent need for effective antiviral therapeutics. In this review, we explore the potential of broad-spectrum antiviral agents targeting respiratory RNA viruses, including influenza viruses, coronaviruses, respiratory syncytial virus, human metapneumovirus, human parainfluenza viruses, and rhinoviruses. Various broad-spectrum direct-acting and host-targeting antivirals are discussed, including monoclonal antibodies targeting conserved regions of viral surface proteins, molecules interfering with host cell receptors or viral replication machinery, viral protease inhibitors, siRNA therapies, ribonuclease, and 3D8 scFv. Advancements in host-targeting approaches to reduce resistance and RNA-based therapeutics offer significant potential for combating respiratory viral threats. Despite challenges, broad-spectrum antiviral agents represent a crucial strategy, particularly when specific viral pathogens are unidentified or rapid intervention is essential, such as during pandemics or outbreaks. Full article
(This article belongs to the Section Molecular Pharmacology)
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