Cancer treatments such as surgery and chemotherapy have several limitations, including ineffectiveness against large or persistent tumors, high relapse rates, drug toxicity, and non-specificity of therapy. Researchers are exploring advanced strategies for treating this life-threatening disease to address these challenges. One promising approach is targeted drug delivery using prodrugs or surface modification with receptor-specific moieties for active or passive targeting. While various drug delivery systems have shown potential for reaching hepatic cells, nano-carriers offer significant size, distribution, and targetability advantages. Engineered nanocarriers can be customized to achieve effective and safe targeting of tumors by manipulating physical characteristics such as particle size or attaching receptor-specific ligands. This method is particularly advantageous in treating liver cancer by targeting specific hepatocyte receptors and enzymatic pathways for both passive and active therapeutic strategies. It highlights the epidemiology of liver cancer and provides an in-depth analysis of the various targeting approaches, including prodrugs, liposomes, magneto-liposomes, micelles, glycol-dendrimers, magnetic nanoparticles, chylomicron-based emulsion, and quantum dots surface modification with receptor-specific moieties. The insights from this review can be immensely significant for preclinical and clinical researchers working towards developing effective treatments for liver cancer. By utilizing these novel strategies, we can overcome the limitations of conventional therapies and offer better outcomes for liver cancer patients.

Deaths from viral hepatitis continue to rise around the world due to the lack of early biomarkers. We aimed here to evaluate the chemokine CXCL14, as a novel biomarker in acute viral hepatitis. We used a mouse model of acute hepatitis induced by murine hepatitis virus (MHV), a hepatotropic and lytic coronavirus, and showed that CXCL14 is overexpressed in the liver and sera of infected mice. Using primary cultures of murine and human hepatocytes, we showed that hepatocytes are the main source of CXCL14 after lytic hepatotropic virus infection and that CXCL14 expression is also induced by the pro-inflammatory cytokines IL-6 and TNFα. CXCL14 KO mice infected with MHV were partially protected and showed an attenuated antiviral immune response compared to wild-type mice. Finally, we show that CXCL14 is overexpressed in the sera of human patients infected with hepatitis viruses A, B, and E or herpes simplex virus. A positive correlation between CXCL14 and ALT levels in the sera of patients with acute herpetic hepatitis, as well as in mice models, suggests that hepatocyte lysis is necessary for the release of CXCL14. Overall, these data highlight that CXCL14 expression is associated with the occurrence of acute viral hepatitis and could be considered an alarmin and a new indicator of inflammation. CXCL14 serum levels are also associated with the severity of viral-induced liver injury.

Porcine epidemic diarrhea virus (PEDV) causes severe intestinal damage and high mortality in neonatal piglets. The continuous emergence of new strains has brought new challenges to prevention and control. In this study, we isolated and characterized a prevalent PEDV virulent strain and analyzed 19,612 jejunal cells from PEDV-infected and control piglets using single-cell sequencing, revealing significant changes in cellular composition, gene expression, and intercellular communication. In response to PEDV infection, epithelial repair was enhanced through increased proliferation and differentiation of stem cells, transit-amplifying (TA) cells, and intestinal progenitor cells into enterocytes. Additionally, PEDV disrupted intercellular communication, compromising epithelial functionality while triggering immune responses, with IFN-γ and IL-10 signaling activation acting as critical regulators of immune balance and tissue homeostasis. Beyond enterocytes, viral genes were detected in various other cell types. Further experiments confirmed that PEDV could initiate replication in B and T lymphocytes but was unable to produce infectious progeny, with T cells additionally undergoing virus-induced apoptosis. These findings provide new insights into PEDV tropism, immune evasion, and epithelial repair, revealing complex host-pathogen interactions that shape disease progression and tissue regeneration, thereby contributing to a better understanding of enteric coronavirus pathogenesis.IMPORTANCEThe persistent circulation of porcine epidemic diarrhea virus (PEDV) poses a major threat to the swine industry, with emerging strains complicating prevention and control efforts. Currently, no effective measures completely prevent virus transmission, highlighting the need to understand PEDV-host interactions. In this study, we isolated a prevalent virulent strain and used single-cell sequencing to identify new PEDV-infected cell types and explore the complex interplay between the host and PEDV. These findings provide essential insights into viral pathogenesis and facilitate the design of targeted antiviral interventions.

Microglia are the primary resident immune cells of the central nervous system (CNS) that respond to injury and infections. Being critical to CNS homeostasis, microglia also have been shown to contribute to neurodegenerative diseases and brain cancer. Hence, microglia are regarded as a potential therapeutic target in CNS diseases, resulting in an increased demand for reliable in vitro models. Two human microglia cell lines (HMC3 and C20) are being used in multiple in vitro studies, however, the knowledge of their biological and immunological characteristics remains limited. Our aim was to identify and compare the biological changes in these immortalised immune cells under normal physiological and immunologically challenged conditions. Using high-resolution quantitative mass spectrometry, we have examined in-depth proteomic profiles of non-stimulated and LPS or IFN-γ challenged HMC3 and C20 cells. Our findings reveal that HMC3 cells responded to both treatments through upregulation of immune, metabolic, and antiviral pathways, while C20 cells showed a response associated with mitochondrial and immune activities. Additionally, the secretome analysis demonstrated that both cell lines release IL-6 in response to LPS, while IFN-γ treatment resulted in altered kynurenine pathway activity, highlighting distinct immune and metabolic adaptations.

Drug-induced cystitis (DIC) significantly impacts patient quality of life and treatment outcomes. This study investigates the incidence and characteristics of DIC using data from the FDA Adverse Event Reporting System (FAERS).

We reviewed FAERS reports related to cystitis from Q1 2004 to Q1 2024, compiling a list of potential causative drugs. The top 50 drugs with the highest number of cystitis reports were ranked. Statistical disproportionality analyses, including Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR), were used to detect unusually high reporting frequencies of cystitis associated with specific drugs.

From 17,703,515 FAERS reports spanning 2004-2024, 36399 involved cystitis. The majority of implicated drugs were antineoplastics. Busulfan, BCG, and mitomycin had the highest ROR and PRR values. Additionally, drugs such as defibrotide sodium, milrinone, and dyazide, which do not have cystitis listed on their labels, were identified, highlighting the need for increased clinical vigilance and awareness.

The findings underscore the importance of ongoing pharmacovigilance in identifying and characterizing DIC. Further clinical studies are warranted to validate these associations and to develop strategies for mitigating the risk of DIC, thereby improving patient safety and treatment outcomes.

The mucosal system serves as the primary barrier against respiratory diseases and plays a crucial role in combating viral infections through mucosal immunity. The resident microbial community constitutes the main component of the mucosal system and exerts a significant inhibitory impact on the invasion of exogenous agents. However, the precise relationship between resident microbiota, mucosal immunity, and viral infections remains incomplete. This review aims to summarize the regulatory interactions between the resident microbiota of the mucosal system and innate immune components such as mucosal immunity and trained immunity. By clarifying these complex relationships, this review seeks to identify potential targets for augmenting respiratory disease prevention strategies and developing novel vaccine formulations. Furthermore, we propose the possibility of integrating the fields of microbiome-based therapeutics and vaccine development to create multifunctional vaccine formulations capable of targeting mucosal immunity induction. Such an approach holds great potential in offering novel pathways and strategies for the prevention and treatment of respiratory diseases.

Orf virus (ORFV) is the type species of Parapoxvirus of the Poxviridae family that induces cutaneous pustular skin lesions in sheep and goats, and causes zoonotic infections in humans. Pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs), leading to the triggering of the innate immune response through multiple signalling pathways involving type I interferons (IFNs). The major PAMPs generated during viral infection are nucleic acids, which are the most important molecules that are recognized by the host. The induction of type l IFNs leads to activation of the Janus kinase (JAK)-signal transducer activator of transcription (STAT) pathway, which results in the induction of hundreds of interferon-stimulated genes (ISGs), many of which encode proteins that have antiviral roles in eliminating virus infection and create an antiviral state. Genetic and functional analyses have revealed that ORFV, as found for other poxviruses, has evolved multiple immunomodulatory genes and strategies that manipulate the innate immune sensing response.

XRN1 (5'-3' exoribonuclease 1) degrades RNA from the 5' → 3' direction and utilizes both single- and double-stranded RNA as substrates. XRN1 plays a critical role in mRNA turnover as well as regulating the cellular response to viral infection. XRN1 also protects the cell by preventing endogenous double-stranded RNA accumulation. XRN1 was identified as a putative vulnerability in a subset of cancer cell lines through analysis of publicly available CRISPR data. The role of XRN1 was explored using a set of non-small cell lung cancer cell lines with differential predicted XRN1 dependency to validate XRN1 as an oncology target. In predicted sensitive cell lines, XRN1 knockout reduced proliferation, increased apoptosis and activated the pPKR and MDA5 dsRNA sensing pathways. To facilitate drug discovery targeting XRN1, a suite of biochemical and biophysical assays was developed. These assays were used to characterize adenosine-3',5'-bisphosphate (pAp), a non-selective nuclease inhibitor, as a nanomolar inhibitor of XRN1. Additionally, the crystal structure of human XRN1 was solved with pAp bound, demonstrating distinct interactions for the compound in the XRN1 active site. These studies provide a strong foundation for the discovery of potent, selective inhibitors of XRN1 as a novel approach to cancer therapeutics.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a significant global public health threat, particularly to older adults, pregnant women, and individuals with underlying chronic conditions. Dysregulated immune responses to SARS-CoV-2 infection are believed to contribute to the progression of COVID-19 in severe cases. Previous studies indicates that a deficiency in type I interferon (IFN-I) immunity accounts for approximately 15 %-20 % of patients with severe pneumonia caused by COVID-19, highlighting the potential therapeutic importance of modulating IFN-I signals. Natural products and their derivatives, due to their structural diversity and novel scaffolds, play a crucial role in drug discovery. Some of these natural products targeting IFN-I have demonstrated applications in infectious diseases and inflammatory conditions. However, the immunomodulatory potential of IFN-I in critical COVID-19 pneumonia and the natural compounds regulating the related signal pathway remain not fully understood. In this review, we offer a comprehensive assessment of the association between IFN-I and severe COVID-19, exploring its mechanisms and integrating information on natural compounds effective for IFN-I regulation. Focusing on the primary targets of IFN-I, we also summarize the regulatory mechanisms of natural products, their impact on IFNs, and their therapeutic roles in viral infections. Collectively, by synthesizing these findings, our goal is to provide a valuable reference for future research and to inspire innovative treatment strategies for COVID-19.

Chronic rhinosinusitis with nasal polyps (CRSwNPs) involves persistent sinus inflammation, with emerging evidence suggesting a potential role of rhinovirus (RV) in its pathophysiology. However, whether RV exists in nasal tissues and affects the nasal mucosa after the resolution of infection symptoms remains unknown.

To investigate the prevalence and impact of silent RV infection in nasal tissues.

RV loads were detected in the nasal tissues of 47 controls and 101 patients with CRSwNP without respiratory infection. Participants were categorized into RV-positive (+), RV-negative (-), and the "gray zone" groups. Quantitative polymerase chain reaction, Western blotting, and immunofluorescence assays were used to analyze the impact of silent RV infection on the immune status of nasal tissues.

Silent RV infection was prevalent in both control (34%) and CRSwNP (30.7%) tissues, with higher viral loads observed in the nasal polyps. In controls, it was associated with high expression of types 1 and 2 interferon (IFN), type 2 inflammation, interleukin (IL)-17A, and IL-10. In patients with CRSwNP, silent RV infection was associated with lower levels of type 1 IFN, IL-17A, type 2 inflammation, and IL-10 but higher levels of type 2 IFN compared with those without RV infection. Meanwhile, RV (+) nasal polyps exhibited fewer tissue eosinophils and neutrophils than RV (-) nasal polyps.

Silent RV infection was prevalent in the nasal tissues, with a higher viral load detected in the nasal polyps. This silent RV infection is associated with distinct immune responses in healthy controls and patients with CRSwNP, involving differential modulation of IFNs, TH2 cytokines, IL-17A, IL-10, and eosinophil and neutrophil levels.

The intricate interplay involving Type I interferon (IFN), anti-interferon antibodies, and COVID-19 elucidates a complex symphony within the immune system. This chapter thoroughly explores the dynamic landscape of Type I IFN, delineating its pivotal role as the guardian of the immune response. As SARS-CoV-2 engages the host, the delicate balance of IFN induction and signaling pathways is disrupted, resulting in a nuanced impact on the severity and pathogenesis of COVID-19. Clinical studies illuminate a critical link between impaired IFN response and severe outcomes, uncovering genetic factors contributing to susceptibility. Furthermore, the emergence of anti-interferon antibodies proves to be a disruptive force, compromising the immune arsenal and correlating with disease severity. Our chapter encompasses diagnostic and prognostic implications, highlighting the importance of assays in identifying levels of IFN and anti-interferon antibodies. This chapter examines the possible incorporation of interferon-related biomarkers in COVID-19 diagnostics, offering predictive insights into disease progression. On the therapeutic front, efforts to manipulate the IFN pathway undergo scrutiny, encountering complexities in light of anti-interferon antibodies. This chapter concludes by outlining prospective avenues for precision medicine, emphasizing the imperative need for a comprehensive comprehension of the IFN landscape and its intricate interaction with COVID-19.

In a subset of SARS-CoV-2-infected individuals treated with the antiviral nirmatrelvir-ritonavir, the virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used a mathematical model to describe the longitudinal viral load dynamics of 51 individuals treated with nirmatrelvir-ritonavir, 20 of whom rebounded. Target cell preservation, either by a robust innate immune response or initiation of N-R near the time of symptom onset, coupled with incomplete viral clearance, appears to be the main factor leading to viral rebound. Moreover, the occurrence of viral rebound is likely influenced by the time of treatment initiation relative to the progression of the infection, with earlier treatments leading to a higher chance of rebound. A comparison with an untreated cohort suggests that early treatments with nirmatrelvir-ritonavir may be associated with a delay in the onset of an adaptive immune response. Nevertheless, our model demonstrates that extending the course of nirmatrelvir-ritonavir treatment to a 10-day regimen may greatly diminish the chance of rebound in people with mild-to-moderate COVID-19 and who are at high risk of progression to severe disease. Altogether, our results suggest that in some individuals, a standard 5-day course of nirmatrelvir-ritonavir starting around the time of symptom onset may not completely eliminate the virus. Thus, after treatment ends, the virus can rebound if an effective adaptive immune response has not fully developed. These findings on the role of target cell preservation and incomplete viral clearance also offer a possible explanation for viral rebounds following other antiviral treatments for SARS-CoV-2.

Nirmatrelvir-ritonavir is an effective treatment for SARS-CoV-2. In a subset of individuals treated with nirmatrelvir-ritonavir, the initial reduction in viral load is followed by viral rebound once treatment is stopped. We show that the timing of treatment initiation with nirmatrelvir-ritonavir may influence the risk of viral rebound. Nirmatrelvir-ritonavir stops viral growth and preserves target cells but may not lead to full clearance of the virus. Thus, once treatment ends, if an effective adaptive immune response has not adequately developed, the remaining virus can lead to rebound. Our results provide insights into the mechanisms of rebound and can help develop better treatment strategies to minimize this possibility.

Dendritic cells (DCs) play a pivotal role in activating naïve T-cells and bridging innate and adaptive immunity. This study aimed to identify and characterize CD83 and CD276 as potential markers for DCs in olive flounder (Paralichthys olivaceus). Specific antibodies against these markers were developed and used to analyze their distribution in peripheral blood leukocytes (PBLs) and intestinal tissues. Flow cytometry and immunohistochemistry revealed that CD83 and CD276 are expressed on DCs, with peak expression observed one week after oral administration of an inactivated viral hemorrhagic septicemia virus (VHSV) vaccine. Gene expression analysis further demonstrated significant activation of immune-related genes, including CD3, IgM, and TLRs, indicating that oral vaccine administration effectively activates the intestinal mucosal immune system. These findings provide valuable insights into fish immune responses and establish CD83 and CD276 as promising DC markers, contributing to the development of mucosal vaccine strategies in aquaculture.

The zinc finger protein 36-like (ZFP36L) family is a CCCH-type group consisting of RNA-binding proteins, i.e., ZFP36L1 and ZFP36L2, which regulate cellular mRNA through the RNA decay pathway. ZFP36L1 combats flavivirus infections through the 5'-3' XRN1 and 3'-5' RNA exosome decay pathways. The present study clarified the role of human ZFP36L2 in the defense response of the host against flavivirus infection.

Cell lines with overexpression or knockdown of ZFP36L2 were established using lentiviral vectors carrying genes for overexpression and short-hairpin RNA targeting specific genes, respectively. A plaque assay was employed to determine the viral titer. Immunofluorescence and real-time quantitative polymerase chain reaction were used to measure the viral RNA levels. The in vitro-transcribed RNA transcript derived from a replication-dead Japanese encephalitis virus (JEV) replicon containing the renilla luciferase reporter gene (J-R2A-NS5mt) was used to assess the stability of the flavivirus RNA. An RNA immunoprecipitation assay was used to detect the protein-RNA binding ability. Confocal microscopic images were captured to analyze protein colocalization.

ZFP36L2 served as an innate host defender against JEV and dengue virus. ZFP36L2 inhibited flavivirus infection solely through the 5'-3' XRN1 RNA decay pathway, whereas ZFP36L1 inhibited JEV infection via the 5'-3' XRN1 and 3'-5' RNA exosome RNA decay pathways. The direct binding between viral RNA and ZFP36L2 via its CCCH-type zinc finger motifs facilitated the degradation of flavivirus RNA mediated by 5'-3' XRN1. Furthermore, ZFP36L2 was localized in processing bodies (PBs), which participate in the 5'-3' XRN1-mediated RNA decay pathway. Nonetheless, the disruption of PBs did not affect the antiviral activity of ZFP36L2, suggesting that its localization is not essential for the function of the protein. Interestingly, the colocalization of ZFP36L2 and XRN1 with viral RNA and NS3 revealed that the antiviral activity of ZFP36L2 occurred within the replication complexes (RCs).

In summary, ZFP36L2 bound to and degraded viral RNA through the XRN1-mediated RNA decay pathway in the RCs, thereby inhibiting flavivirus replication. These findings provide valuable insights into the diverse antiviral mechanisms of the ZFP36-like family of proteins in the innate immune response against flavivirus infection.

Bovine herpesvirus type 1 (BoHV-1) is a widespread respiratory infection that significantly impacts cattle health worldwide. To address this issue in China, we previously developed a novel double gene-deleted vaccine targeting gG and tk. In this study, we further evaluated the efficacy of this vaccine by challenging vaccinated cattle with a prevalent wild-type BoHV-1 strain and comparing its effectiveness against a commercially available inactivated BoHV-1 vaccine. Post-immunization, all cattle maintained normal rectal temperatures and exhibited no respiratory symptoms. Cattle receiving the gene-deleted vaccine showed a significant increase in the expression of immune markers IFN-γ and TNF-α. Following exposure to wild-type BoHV-1, all immunized groups produced high levels of neutralizing antibodies and specific gB antibodies. Notably, virus shedding was significantly lower in the vaccinated groups compared to the non-immune challenge group. Histological analysis of lung tissues revealed that vaccinated calves had more intact lung structure than their unimmunized counterparts after the challenge. Additionally, the gG-/tk- gene-deleted vaccine demonstrated a higher protective rate based on the average scores of clinical symptoms and lung lesions. Overall, the BoHV-1 gG-/tk- gene-deleted vaccine outperformed the other vaccines tested. This study confirms that the gene-deleted vaccine provides robust protection and superior immunogenicity compared to existing inactivated vaccines, underscoring its potential for future market application.

Inflammation is a significant driver of ischemic stroke pathology in the brain. To identify potential regulators of inflammation, we performed single-cell RNA sequencing (scRNA-seq) of young and aged mouse brains following stroke and found that interferon alpha-inducible protein 27 like 2 A (Ifi27l2a) was significantly up-regulated, particularly in microglia of aged brain. Ifi27l2a is induced by interferons for viral host defense and has been linked with pro-inflammatory cellular mechanisms. However, its potential role in neurodegeneration is unknown. Using a combination of cell culture, experimental stroke models in mice, and human autopsy brain samples, we demonstrated that induction of Ifi27l2a occurs in microglia in response to aging, ischemic stroke, and pro-inflammatory molecules. We further showed that induction of Ifi27l2a in microglia was sufficient to stimulate mitochondrial ROS production and promote a pro-inflammatory phenotype. Lastly, using an ischemic stroke model, we demonstrated that hemizygous deletion of Ifi27l2a (Ifi27l2a+/- mice) reduced gliosis (microgliosis and astrogliosis), acute and chronic brain injury, and motor function deficits. Together, these findings identify Ifi27l2a as a critical neuroinflammatory mediator in ischemic stroke and provide support for the therapeutic strategy of disrupting Ifi27l2a to attenuate inflammation in the post-stroke brain.

The treatment landscape for hepatitis C virus (HCV) infection has transformed over the past few decades, evolving from the limited efficacy of interferon (IFN) monotherapy to the highly successful pan-genotypic direct-acting antivirals (DAAs) used today. Initially, alpha-interferon monotherapy, introduced in the 1990s, was the standard treatment, yet it provided low sustained virological response (SVR) rates and caused significant adverse effects, limiting its utility. The development of pegylated interferon (peg-IFN) improved the pharmacokinetic profile of IFN, allowing for less frequent dosing and modestly improved response rates. When combined with ribavirin, peg-IFN achieved higher SVR rates, especially in non-genotype 1 HCV infections, but the combination also brought additional side effects, such as anemia and depression. The advent of the first-generation DAAs, such as telaprevir and boceprevir, marked a significant milestone. Combined with peg-IFN and ribavirin, these protease inhibitors boosted response rates in patients with genotype 1 HCV. However, high rates of adverse effects and drug resistance remained challenges. Second-generation DAAs, like sofosbuvir and ledipasvir, introduced IFN-free regimens with improved safety profiles and efficacy. The most recent advances are pan-genotypic DAAs, including glecaprevir-pibrentasvir and sofosbuvir-velpatasvir, which offer high SVR rates across all genotypes, shorter treatment durations, and fewer side effects. Current pan-genotypic regimens represent a cornerstone in HCV therapy, providing an accessible and effective solution globally.

Interferons (IFNs) are a diverse family of cytokines secreted by various cells, including immune cells, fibroblasts, and certain viral-parasitic cells. They are classified into three types and encompass 21 subtypes based on their sources and properties. The regulatory functions of IFNs closely involve cell surface receptors and several signal transduction pathways. Initially investigated for their antiviral properties, IFNs have shown promise in combating cancer-associated viruses, making them a potent therapeutic approach. Most IFNs have been identified for their role in inhibiting cancer; however, they have also demonstrated cancer-promoting effects under specific conditions. These mechanisms primarily rely on immune regulation and cytotoxic effects, significantly impacting cancer progression. Despite widespread use of IFN-based therapies in viral-related cancers, ongoing research aims to develop more effective treatments. This review synthesizes the signal transduction pathways and regulatory capabilities of IFNs, highlighting their connections with viruses, cancers, and emerging clinical treatments.

Ulvans, abundant natural polysaccharides produced by Ulvales, have been recognized for antiviral activities, though the underlying mechanisms are not fully understood. In this study, we focused on two polysaccharides and one oligosaccharide, which were extracted enzymatically from Ulva prolifera and named as PR1 (13.5 kDa), PR2 (7.1 kDa) and PR3 (0.6 kDa), respectively. Comprehensive analyses of structures and monosaccharide composition revealed a primary composition of L-rhamnose, D-glucuronic acid and D-xylose. Of particular interest, PR1 showed a pronounced ability to inhibit vesicular stomatitis virus (VSV) in macrophages, demonstrated by an IC50 value of 179.1 ± 29.8 ng/mL. In A549 cells, a human lung carcinoma line, PR1 displayed moderate antiviral activity. However, in IFN-deficient Vero cells, PR1 proved ineffective, suggesting that PR1 might exert antiviral effects through type I interferon. A significant finding of this study is that PR1 is capable of entering cells in an energy-dependent manner, a characteristic previously undocumented. Moreover, PRs were observed to activate the intracellular STING signaling pathway, leading to the phosphorylation and subsequent nuclear translocation of p65 and IRF3. This novel discovery enhances our understanding of ulvan's role in immune modulation, highlighting the importance of considering intracellular proteins and pathways when investigating the mechanisms of polysaccharides.

The viral replication can impress through cellular miRNAs. Indeed, either the antiviral responses or the viral infection changes through cellular miRNAs resulting in affecting many regulatory signaling pathways. One of the microRNA families that is effective in human cancers, diseases, and viral infections is the miR-29 family. Members of miR-29 family are effective in different viral infections as their roles have appeared in regulation of immunity pathways either in innate immunity including interferon and inflammatory pathways or in adaptive immunity including activation of T-cells and antibodies production. Although miR-29a affects viral replication by suppressing antiviral responses, it can inhibit the expression of viral mRNAs via binding to their 3'UTR. In the present work, we discuss the evidence related to miR-29a and viral infection through host immunity regulation. We also review roles of other miR-29 family members by focusing on their role as biomarkers for diagnosing and targets for viral diseases management.

COVID-19 is an emerging viral pandemic caused by SARS-CoV-2, which is the causative agent of unprecedented disease-causing public health threats globally. Worldwide, this outbreak is wreaking havoc due to failure in risk assessment regarding the urgency of the pandemic. As per the reports, many secondary complications which include neurological, nephrological, gastrointestinal, cardiovascular, immune, and hepatic abnormalities, are linked with COVID -19 infection which is associated with prominent respiratory disorders including pneumonia. Hindering the initial binding of the virus with Angiotensin-converting enzyme 2 (ACE2) through the spike protein is one potential boulevard of monoclonal antibodies. Although some drug regimens and vaccines have shown safety in trials, none have been entirely successful yet. This review highlights, some of the potential antibodies (tocilizumab, Sarilumab, Avdoralimab, Lenzilumab, Interferon (alfa /beta /gamma)) screened against SARS-CoV-2 and the most promising drugs (Favipiravir, Hydroxychloroquine, Niclosamide, Ribavirin, Baricitinib, Remdesivir, Arbidol Losartan, Ritonavir, Lopinavir, Baloxavir, Nitazoxanide, Camostat) in various stages of development with their synthetic protocol and their clinical projects are discussed to counter COVID -19.

Influenza A virus (FLUAV) causes serious diseases in both poultry and humans. Various host proteins, including Mx1, are considered candidates for avian influenza (AI) resistance. After infecting Jeju Native chicken embryo fibroblasts (CEFs) with three types of AI viruses, we performed gene expression profiling, identified single nucleotide polymorphisms (SNPs) through RNA-sequencing, and confirmed phenotypes showing antiviral activity in vitro. Highly pathogenic AI viruses upregulated FGF2, LYN, and FLT4 and downregulated HGF, ANGPT1, and ROR2, while a low pathogenicity AI upregulated PARK7, RACK1, and DTX3L and downregulated SIRT1, LRRK2, and WAC. However, no virus affected Mx1 expression. Although SNPs in Mx1 could not discriminate antiviral activity alone, the only CEF resistant to H5N6, strain AN4, contained the Mx1 631 R/R genotype and strongly expressed an oligoadenylate synthetase-like (OASL) variant with a unique SNP: c.G880A (p.E294K). Using transfected cell lines, H5N6-infected cells expressing OASL with the c.G880A SNP showed minimal cytopathic effects and the lowest M gene expression. This study confirms that Jeju Native chickens with specific SNP combinations in both Mx1 and OASL showed H5N6 resistance and demonstrates the interplay of genetic factors in host-pathogen dynamics, suggesting a need for integrated analyses of multiple resistance genes to inform AI prevention strategies.

Pseudorabies virus (PRV) establishes persistent latent infections by effectively evading the host's antiviral innate immune response. PRV has developed sophisticated strategies to bypass immune surveillance through coevolution with its host. Currently, no effective vaccine exists to prevent or treat infections caused by emerging PRV variants, and the interactions between PRV and the host's innate immune defenses remain incompletely understood. Nevertheless, ongoing research is uncovering insights that may lead to novel treatments and preventive approaches for herpesvirus-related diseases. This review summarizes recent advances in understanding how PRV disrupts key adaptors in immune signaling pathways to evade antiviral immunity. Additionally, we explored the intrinsic cellular defenses that play crucial roles in combating viral invasion. A deeper understanding of the immune evasion strategies of PRV could inform the development of new therapeutic targets and vaccines.

Breast cancer is the most common malignancy among women worldwide, characterized by complex molecular and cellular heterogeneity. Despite advances in diagnosis and treatment, there is an urgent need to identify reliable biomarkers and therapeutic targets to improve early detection and personalized therapy. The OAS (2'-5'-oligoadenylate synthetase) family genes, known for their roles in antiviral immunity, have emerged as potential regulators in cancer biology. This study aimed to explore the diagnostic and functional relevance of OAS family genes in breast cancer.

Breast cancer cell lines and controls were cultured under specific conditions, and DNA and RNA were extracted for downstream analyses. RT-qPCR, bisulfite sequencing, and Western blotting were employed to assess gene expression, promoter methylation, and knockdown efficiency of OAS family genes. Functional assays, including CCK-8, colony formation, and wound healing, evaluated cellular behaviors, while bioinformatics tools (UALCAN, GEPIA, HPA, OncoDB, cBioPortal, and others) validated findings and explored correlations with clinical data.

The OAS family genes (OAS1, OAS2, OAS3, and OASL) were found to be significantly upregulated in breast cancer cell lines and tissues compared to normal controls. This overexpression was strongly associated with reduced promoter methylation. Receiver operating characteristic (ROC) analysis demonstrated high diagnostic accuracy, with area under the curve (AUC) values exceeding 0.93 for all four genes. Increased OAS expression correlated with advanced cancer stages and poor overall survival in breast cancer patients. Functional analysis revealed their involvement in critical biological processes, including immune modulation and oncogenic pathways. Silencing OAS genes in breast cancer cells significantly inhibited cell proliferation and colony formation, while unexpectedly enhancing migratory capacity. Additionally, correlations with immune cell infiltration, molecular subtypes, and drug sensitivity highlighted their potential roles in the tumor microenvironment and therapeutic response.

The findings of this study established OAS family genes as potential biomarkers and key players in breast cancer progression, offering promise as diagnostic biomarkers and therapeutic targets to address unmet clinical needs.

Hepatitis B virus (HBV) is a hepatotropic DNA virus that can cause acute or chronic hepatitis, representing a significant global health concern. By 2019, approximately 296 million individuals were chronically infected with HBV, with 1.5 million new cases annually and 820,000 deaths due to HBV-related cirrhosis and liver cancer. Current treatments for chronic hepatitis B include nucleotide analogs (NAs) and interferons (IFNs), particularly IFN-α. NAs, such as entecavir and tenofovir, inhibit viral reverse transcription, while IFN-α exerts antiviral effects by directly suppressing viral replication, modulating viral genome epigenetics, degrading cccDNA, and activating immune responses. Despite its potential, IFN-α shows limited clinical efficacy, partly due to HBV's interference with the IFN signaling pathway. HBV encodes proteins like HBc, Pol, HBsAg, and HBx that disrupt IFN-α function. For example, HBV Pol inhibits STAT1 phosphorylation, HBsAg suppresses STAT3 phosphorylation, and HBx interferes with IFN-α efficacy through multiple mechanisms. Additionally, HBV downregulates key genes in the IFN signaling pathway, further diminishing IFN-α's antiviral effects. Understanding these interactions is crucial for improving IFN-α-based therapies. Future research may focus on overcoming HBV resistance by targeting viral proteins or optimizing IFN-α delivery. In summary, HBV's ability to resist IFN-α limits its therapeutic effectiveness, highlighting the need for new strategies to enhance treatment outcomes.

African swine fever (ASF), a highly virulent viral infection, poses a significant threat to the global pig industry. Currently, there are no commercially available vaccines against ASF. While the crucial role of interferon (IFN) in combating viral infections is well-established, its impact on the clinical signs and mortality rates of ASF remains unclear. In this study, swine IFN-α2, IFN-γ, and IFN-λ3 were fused with the Fc segment of immunoglobulin G (IgG) and expressed in mammalian cells (293T), and the antiviral efficacy were detected by VSV-3D4/2 and VSV-PK15 systems. Then, the interferon stimulating genes (ISGs) induced by IFNs-hFc in 3D4/2 cells were determined by qRT-PCR. Also, the preventive potential of the interferon (IFN) cocktail (a mixture of IFNα2-hFc, IFNγ-hFc, and IFNλ3-hFc) were evaluated in vivo by 25-day-old piglets. The results showed that the specific activities of IFNα2-hFc, IFNγ-hFc, and IFNλ3-hFc were 2.46 × 107 IU/mL, 4.54 × 109 IU/mL and 7.54 × 1010 IU/mL, respectively. The IFN-hFc significantly induced the expression of various IFN-stimulated genes (ISGs) in 3D4/2 cells after IFNs-Fc treatment, including IFIT5, Mx1, OASL, ISG12, STAT1, IRF1, PKR, CXCL10, and GBP1. Furthermore, the IFN cocktail treatment reduced the viral load, delayed death, and reduced tissue injury in the piglets infected with ASF virus (ASFV). in conclusion, these results suggest that the IFNs-hFc showed high anti-viral activity, and the IFN cocktail may be potential for the prevention and treatment of ASF.

Interferon-αs (IFN-αs) are crucial cytokines for inducing protective antiviral responses. The baculovirus-mediated gene transduction of mammalian cells (BacMam) is an efficient delivery tool for recombinant protein expression in mammalian cells. This study focuses on the delivery of bovine IFN-α (BoIFNα) using the BacMam system. A recombinant pACEMam1-BoIFNα bacmid was constructed, and a recombinant BacMam-BoIFNα virus was obtained. After transducing HEK293T cells with this virus, BoIFNα protein was successfully secreted into the cell supernatant, displaying antiviral activities against VSV, BPIV3, BEV, and BVDV in bovine-derived cells. Additionally, the BacMam-BoIFNα virus inhibited the replication of these viruses in MDBK cells, induced the transcription of ISGs, and the expression of M × 1 in both MDBK and BT cells. These induction effects were significantly reduced following treatment with a JAK1 inhibitor, suggesting that the BacMam-BoIFNα virus exerts antiviral activity in MDBK cells through JAK-STAT signaling pathway. Furthermore, the study found that the BacMam-BoIFNα virus significantly inhibited the replication of BPIV3 in the lung and trachea of mice. Overall, this study demonstrates that the BacMam-BoIFNα virus have antivirus activities both in vitro and in vivo, signaling through JAK-STAT pathway, and provides an efficient interferon gene delivery tool for combating bovine viral infections.

Recent studies highlight the critical involvement of long non-coding RNAs (lncRNAs) in modulating viral replication and immune responses, yet their specific roles in flavivirus infections remain underexplored. Our study has identified lncRNA SUN2-AS1, which is significantly upregulated in response to flavivirus infection in A549, Huh7 cells, and monocyte-differentiated macrophages (MDMs). SUN2-AS1 interacts with the transcription factors NF-κB and STAT1, andits expression is induced by ZIKV RNA via the type I interferon (IFN) pathway. Notably, SUN2-AS1 enhances the infection of flaviviruses, including ZIKV, DENV2, and JEV, while showing no effect on VSV or HSV-1 infections. Mechanistically, SUN2-AS1 exerts a proviral effect by inhibiting the transcription of interferon-stimulated genes (ISGs). These findings uncover a novel mechanism by which lncRNAs facilitate flavivirus propagation and highlight SUN2-AS1 as a potential target for antiviral therapeutic strategies.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly variable virus with genetic diversity. This study comparatively examines the pathogenicity and immunological impact of two emergent PRRSV strains, SD53 and HuN4, in piglets. Our results indicate that SD53 strain induces milder clinical syndromes and less severe tissue damage than HuN4, despite similar replication rates. Hematological tests showed less perturbations in peripheral blood cell profiles after SD53 infection, suggesting a less systemic impact. The neutrophil-to-lymphocyte ratio was notably lower in SD53-infected piglets, suggesting a less intense inflammatory reaction. Moreover, SD53 infection led to lower levels of pro-inflammatory cytokines, further supporting a less pronounced inflammatory profile. Both strains induced the production of PRRSV-specific antibodies. However, transcriptomic analysis of lung and lymph node tissues from infected piglets disclosed a more moderate up-regulation of core genes, including ISGs, in the SD53 group. Further analysis indicated that SD53 primarily enhanced immune-related signaling, particularly in T cell response modules, while HuN4 caused a more robust pro-inflammatory reaction and a dampening of T cell functionality. Flow cytometry analyses confirmed these findings, showing higher CD4/CD8 ratios and increased CD4+ T cell percentages in SD53-infected piglets, implying a more robust T cell response. Collectively, these findings broaden our comprehension of PRRSV pathogenesis and may inform the development of future therapeutic or prophylactic strategies for controlling PRRSV infections more effectively.

The high mutation rate of porcine reproductive and respiratory syndrome virus (PRRSV) poses significant challenges to its accurate diagnosis and the implementation of effective control measures. This research explores the pathogenic profiles of two emerging PRRSV stains: the NADC30-like strain SD53 and the highly pathogenic strain HuN4. Our investigation reveals that SD53 initiates distinct immunopathological responses in vivo compared with those provoked by HuN4. By conducting a transcriptome analysis of differential gene expression in the lungs and lymph nodes of infected piglets, we unveil the intricate molecular mechanisms underlying the contrasting pathogenicity of these two strains. The comprehensive insights yielded by this study are instrumental in advancing our understanding of the dominant NADC30-like PRRSV strain, which has become increasingly prevalent in China's swine industry.

Studying the early events that occur after viral infection in humans is difficult unless one intentionally infects volunteers in a human challenge study. Here, we use data about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in such a study in combination with mathematical modeling to gain insights into the relationship between the amount of virus in the upper respiratory tract and the immune response it generates. We propose a set of dynamic models of increasing complexity to dissect the roles of target cell limitation, innate immunity, and adaptive immunity in determining the observed viral kinetics. We introduce an approach for modeling the effect of humoral immunity that describes a decline in infectious virus after immune activation. We fit our models to viral load and infectious titer data from all the untreated infected participants in the study simultaneously. We found that a power-law with a power h < 1 describes the relationship between infectious virus and viral load. Viral replication at the early stage of infection is rapid, with a doubling time of ~2 h for viral RNA and ~3 h for infectious virus. We estimate that adaptive immunity is initiated ~7 to 10 d postinfection and appears to contribute to a multiphasic viral decline experienced by some participants; the viral rebound experienced by other participants is consistent with a decline in the interferon response. Altogether, we quantified the kinetics of SARS-CoV-2 infection, shedding light on the early dynamics of the virus and the potential role of innate and adaptive immunity in promoting viral decline during infection.

Drug-induced urinary retention (DIUR) can severely impact patient quality of life and complicate treatment. This study investigates the incidence and characteristics of DIUR using data from the FDA Adverse Event Reporting System (FAERS) over 20 years.

FAERS reports related to urinary retention (UR) from Q1 2004 to Q1 2024 were analyzed. Potential causative drugs were identified, and the top 30 drugs with the most UR reports were ranked. Statistical disproportionality analyses, including Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR), were conducted to detect significant safety signals.

Out of 17,703,515 reports in the FAERS database 28,423 cases of UR were identified. Anticholinergics, antidepressants, and opioids were the most frequently implicated drug classes. The highest ROR and PRR values were observed for drugs like ezogabine. Additionally, less commonly associated drugs, such as adalimumab and others, were implicated, suggesting potential under-recognition of this adverse effect. However, these associations should be interpreted with caution, as they do not confirm a direct causal relationship.

This study underscores the importance of pharmacovigilance in identifying and understanding DIUR. Further research is needed to confirm these findings and develop strategies to manage and reduce the risk, improving patient outcomes.

Largemouth bass virus (LMBV) is a highly pathogenic pathogen that often causes high mortality of affected largemouth bass and significant financial losses. Type I interferon as an effective and broad spectrum tool has been successfully used for therapeutic or prophylactic treatment some viral infections. However, the implementation of immunotherapies based on interferon administration to combat LMBV infections has not been reported. And Lactic Acid Bacteria (LAB) are a powerful vehicle for expressing cytokines or immunostimulant peptides at the gastrointestinal level after oral administration. In this study, Lactococcus lactis (L. lactis) expression system with lactose as a screening marker was utilized to express the Micropterus salmoides interferon a3 (IFNa3) protein and orally administered to largemouth bass. The genetically engineered strain pNZ8149-Usp45-IFNa3-6His/L. lactis NZ3900 was successfully constructed, and its potential to elicit immune protection response by oral administration was evaluated. After orally administration, the recombinant L. lactis was detected in guts of experimental fish and remained detectable for 72 h. Additionally, IFNa3 was able to enhance the test fish's immune response, as determined by the relatively increased mRNA relative expression of immune-related genes in the liver, spleen, and kidney tissues, including IFN-γ, TNF-α, IL-1β, IL-8, IgM and IgT. Following LMBV challenge, the experiment group of pNZ8149-Usp45-IFNa3-6His/L. lactis NZ3900 exhibited a 70 % survival rate, while survival rate were 15 % in the PBS control group, 45 % in the pNZ8149/L. lactis NZ3900 group. Furthermore, the viral load in the surviving fish was significantly lower than that of the control groups. These findings suggest that oral administration of recombinant L. lactis producing IFNa3 induces largemouth bass immune responses at a systemic level to effective prevent and combat of LMBV infection.

Type I Interferons (IFNs) generally have a protective role during viral infections, but their function during bacterial infections is dependent on the bacterial species. Legionella pneumophila, Shigella sonnei and Mycobacterium tuberculosis can inhibit type I IFN signaling. Here we examined the role of type I IFN, specifically IFNβ, in the context of Salmonella enterica serovar Typhimurium (STm) macrophage infections and the capacity of STm to inhibit type I IFN signaling. We demonstrate that IFNβ has no effect on the intracellular growth of STm in infected bone marrow derived macrophages (BMDMs) derived from C57BL/6 mice. STm infection inhibits IFNβ signaling but not IFNγ signaling in a murine macrophage cell line. We show that this inhibition is independent of the type III and type VI secretion systems expressed by STm and is also independent of bacterial phagocytosis. The inhibition is Toll-like receptor 4 (TLR4)-dependent as the TLR4 ligand, lipopolysaccharide (LPS), alone is sufficient to inhibit IFNβ-mediated signaling. Cells downregulated their surface levels of IFNα/β receptor 1 (IFNAR1) in response to LPS, which may be mediating our observed inhibition. Lastly, we examined this inhibition in the context of TLR4-deficient BMDMs as well as TLR4 RNA interference and we observed a loss of inhibition with LPS stimulation as well as STm infection. In summary, we show that macrophages exposed to STm have reduced IFNβ signaling via crosstalk with TLR4 signaling, which may be mediated by reduced host cell surface IFNAR1, and that IFNβ signaling does not affect cell-autonomous host defense against STm.