Search Results (13,493)

The emergence of SARS-CoV-2 variants and antiviral resistance highlights the need for improved therapeutic strategies against COVID-19 and other coronavirus infections. By pairing direct-acting antivirals with repurposed host-modulating drugs, combination therapy approaches may enhance antiviral efficacy while mitigating inflammation. In this study, we evaluated the effects of combining Nirmatrelvir (a SARS-CoV-2 main protease inhibitor) with Ivermectin, Azithromycin or Doxycycline—using a murine hepatitis virus (MHV) infection model of RAW264.7 macrophages. Checkerboard assays demonstrated that the Nirmatrelvir–Ivermectin combination exhibited strongly synergistic antiviral activity. This combination achieved potent inhibition of live virus titer of at least 5 to 6 log₁₀ and reduction in viral RNA load of 3 log₁₀, at drug concentrations much lower than the respective monotherapies. The Nirmatrelvir–Ivermectin combination treatment affected the coronavirus replication cycle at the same time-point of 8 h as Nirmatrelvir monotherapy. Moreover, multiplex cytokine protein profiling revealed that Nirmatrelvir–Ivermectin markedly suppressed key pro-inflammatory cytokines and chemokines associated with the cytokine storm, including IL-6, TNF-α, IL-1β, and MCP-1. Conversely, the combinations of Nirmatrelvir with Azithromycin or Doxycycline exhibited only additive or mildly additive effects, with alterations in certain cytokine levels. These findings support the potential of Nirmatrelvir–Ivermectin as a promising novel combination therapy with both antiviral and anti-inflammatory benefits, warranting further in vivo validation and clinical investigation. Full article

The geographic range and outbreak intensity of vector-borne viral infections are increasing as climate, land use, urbanization, and human mobility reshape vector ecology and human exposure. Despite their growing importance to public health, effective antiviral and preventive options remain limited for many emerging and reemerging vector-borne viruses due to viral genetic diversity, rapid evolutionary capacity, sporadic outbreak patterns, and economic constraints. While these viruses differ in taxonomy, genome organization, vector specificity, tissue tropism, and clinical manifestations, they exploit a shared vulnerability in host antiviral defense, particularly the timing of innate antiviral immunity to support viral replication, immune evasion, inflammatory dysregulation, and disease progression. Rather than simply suppressing antiviral defense, vector-borne viruses can delay early viral nucleic acid sensing, attenuate interferon induction or responsiveness, and extend the initial phase for viral replication. As viral burden increases and infected tissues undergo stress or damage, delayed immune activation can shift toward excessive inflammatory amplification, contributing to disease-specific pathology. In this study, we examine this temporal rewiring of innate antiviral immunity in representative vector-borne viruses such as dengue virus, chikungunya virus, and severe fever with thrombocytopenia syndrome virus and propose that understanding these conserved host dependencies may lead to broader, stage-specific, adaptable antiviral strategies that complement conventional virus-directed approaches. Full article

Superoxide dismutase 2 (SOD2), a key mitochondrial antioxidant enzyme, is essential for maintaining cellular redox homeostasis by scavenging superoxide radicals. While viruses often induce oxidative stress, the specific role of SOD2 in antiviral defense remains unclear. Here, we report that vaccinia virus (VACV) infection triggers mitochondrial and cellular reactive oxygen species (ROS) and selectively upregulates SOD2, but not SOD1. Genetic knockout of SOD2 exacerbated mitochondrial ROS (mtROS) accumulation and significantly enhanced VACV replication and spread, resulting in larger viral plaques. Conversely, SOD2 overexpression constrained plaque formation and suppressed viral dissemination. Mechanistically, the antiviral function of SOD2 does not strictly rely on its enzymatic activity or mitochondrial targeting, as neither the deacetylation-mimicking mutant nor the mutant lacking the mitochondrial localization signal peptide appreciably impaired its antiviral potency. Furthermore, in a rabbit model, local overexpression of human SOD2 attenuated the poxvirus lesion formation. Our findings unveil an important yet easily overlooked role of SOD2 in antiviral defense and posit it as a promising candidate for the development of host-directed therapeutics against poxviruses. Full article

Background and Objectives: Oral antiviral agents nirmatrelvir/ritonavir (NMV/r) and molnupiravir are recommended for the early treatment of non-hospitalized adults with COVID-19 who are at increased risk of disease progression. Real-world comparative data on these two agents remain limited. The aim of this study was to evaluate the efficacy and safety of NMV/r and molnupiravir in non-hospitalized patients with COVID-19. Materials and Methods: We conducted a retrospective, single-center study with a sample size of 122 initially non-hospitalized adults with confirmed SARS-CoV-2 infection treated at the Clinic for Infectious Diseases, University Clinical Center of Vojvodina (UCCV), Novi Sad, Serbia, during 2022. Patients were treated within the first five days of symptom onset with either NMV/r (n = 48) or molnupiravir (n = 74) for five days. Demographic characteristics, clinical presentation, comorbidities, vaccination status, laboratory parameters at baseline and on day 3, chest radiography findings, hospitalization, and mortality were analyzed. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS), version 21 (IBM Corp., Armonk, NY, USA). Results: The groups did not differ significantly in age, sex, vaccination status, or vaccine type. Between baseline and day 3, the increase in lymphocyte count (p < 0.001) was significantly greater in the molnupiravir group. Chest radiography showed no significant between-group differences. Overall, 6 patients (4.9%) were hospitalized, with no significant difference between antiviral agents (p = 1.000), and no deaths occurred. Among patient-reported symptoms effects, the incidence of dysgeusia was significantly higher in patients treated with NMV/r (p = 0.001). Conclusions: Both antivirals showed similarly low progression, hospitalization, and mortality rates. Full article

The human placenta plays a critical role as an immune and mechanical barrier. Notwithstanding, viral pathogens can still cross this barrier. Previously, differential gene expression has been described for protein-coding genes in human-induced-pluripotent-stem-cell-derived (hiPSC-derived) trophoblasts (TBs) from dizygotic twins discordant for congenital Zika syndrome (CZS), in which only one of the twin subjects presented the microcephaly phenotype. However, the involvement of long non-coding RNAs (lncRNAs) in TB development and in the TB response to ZIKV infection remained unexplored. To address this gap, we constructed a trophoblast-specific, lncRNA-enriched transcriptome resource and used it to define co-expression networks linking lncRNAs to trophoblast differentiation and to the antiviral response to ZIKV infection. Here, public RNA-Seq data from hiPSCs and hiPSC-derived TBs from dizygotic twins discordant for CZS were re-mapped to the human reference genome (GRCh38) using an ad hoc compiled hiPSC-TB-specific transcriptome enriched for lncRNAs, followed by differential expression analysis, co-expression network analysis and gene ontology (GO) enrichment. Expression validation by RT-qPCR of a set of novel and known lncRNAs associated with trophoblast differentiation and ZIKV infection was obtained. When comparing hiPSCs and TBs, 218 known and 26 novel lncRNAs were differentially expressed (DE) (FDR < 0.001). Correlated modules were enriched with GO terms related to “epithelial cell differentiation” and “tissue morphogenesis”. Upon comparing TBs derived from the dizygotic twins, before and after ZIKV infection, 96 known and 6 novel lncRNAs were DE (FDR < 0.05). Correlated modules were enriched with interferon-related GO terms, including “regulation of defense response to virus” and “response to interferon”. ZIKV-infected TBs from microcephaly-affected twins showed a 2.5-fold lower number of DE protein-coding genes and a 2-fold lower number of DE lncRNAs, compared with ZIKV-infected TBs from non-affected twins. These results indicate lncRNAs associated with TB development and response to ZIKV infection, highlighting candidates to be prioritized in future functional studies, such as CARINH, PSMB8-AS1, HCP5, BISPR and imprinted H19 and MEG3 lncRNAs. Full article

Indoles are chemical compounds that naturally occur in Prokaryotes and Eukaryotes. For example, indole alkaloids mainly occur in plant families such as Nyssaceae, Rubiaceae, Apocynaceae, and Loganiaceae. The popularity of indoles has led to further research into their function and synthetic modification. Meanwhile, the Wnt (Wingless and Int-1) signaling pathway is responsible for cell regulatory processes, while its dysfunction often constitutes the molecular basis for the pathogenesis of neoplastic processes. Databases such as PubMed, Scopus, Google Scholar, and Science Direct were used to perform a literature search with keywords including “indoles” and those related to their biological activity, as well as “Wnt pathway” and “thyroid cancer (TC)”. We used ClinicalTrials.gov to search current clinical trials for selected indoles, such as melatonin, indole-3-propionic acid, and indole-3-carbinol. While indoles possess many therapeutic properties, we focused here on the following: antitumor, antiviral, anti-inflammatory, antidepressant, antimigraine, antiemetic, and antihypertensive activities. We analyzed the Wnt pathway and its disruptions in thyroid cancer. In this manuscript, seventy-six (76) indoles, which have natural and synthetic origins, are presented. In addition to all activities mentioned, we discuss the therapeutic goals of indole applications in anticancer research. The Wnt signaling pathway can be changed in tumor cells, and such disruptions can occur in thyroid cancers. Full article

The hepatitis B virus (HBV) is a worldwide hepatotropic virus despite the availability of a highly effective vaccine. Currently, the most efficacious treatment against HBV infection is the use of interferon and nucleos(t)ide analogs, which effectively suppress viral replication but do not eradicate infection. Consequently, studies are still ongoing to identify novel molecules with antiviral properties. Interfering with HBV trafficking in infected cells is an approach that would greatly benefit from the diverse techniques of microscopy. However, several challenges arise in employing such techniques for HBV, given the unique characteristics of this virus. Notably, HBV predominantly produces non-infectious subviral particles in addition to infectious virions. Moreover, both virions and SVPs are small objects, measuring only 20 to 40 nm, which challenges their observation using conventional optical microscopy. Additional obstacles include the small size of the HBV genome and its high compaction, which restrict reverse genetics and the introduction of DNA sequences coding for fluorescent polypeptides. In this review, we will provide an overview of ongoing research efforts aimed at visualizing the different stages of the HBV life cycle within infected cells. Furthermore, we will explore solutions successfully applied to the visualization of other viruses that could potentially be adapted to HBV. Full article

Kidney transplant recipients (KTRs) face a significantly elevated risk of persistent high-risk human papillomavirus (HR-HPV) infection and subsequent anal squamous cell carcinoma (ASCC) due to chronic immunosuppressive therapy impairing immunosurveillance. Despite the markedly increased risk of ASCC in this vulnerable cohort, standardized screening protocols and optimal clinical management guidelines are not exhaustive. Chronically compromised immunosurveillance permits prolonged HR-HPV carriage and viral genome integration, driving oncogenesis via the E6 and E7 oncoproteins. While calcineurin inhibitors exert pro-oncogenic effects, transitioning to mTOR inhibitors offers distinct antiproliferative and antiviral advantages. Early detection relies on risk-stratified screening utilizing digital anorectal examination, anal cytology, and high-resolution anoscopy. For managing anal intraepithelial neoplasia, traditional topical agents and minimally invasive ablative procedures are widely used, although high recurrence rates present a major clinical challenge. This review analyzes HPV pathogenesis and clinical management in KTRs, evaluating the impact of immunosuppressive regimens and exploring innovative diagnostic and therapeutic strategies. To address viral persistence without compromising the allograft, integrating novel non-invasive, target-specific nutraceuticals may represent an interesting complementary approach. Ultimately, mitigating post-transplant ASCC requires a multidisciplinary strategy that couples early localized screening with tailored systemic immunosuppression. Full article

Chronic hepatitis B (CHB) infection is a major risk factor for progressive cirrhosis and hepatocellular carcinoma. Persistent virus-induced inflammation alters liver function, leading to accelerated disease and increased mortality. Although lifelong treatment with nucleos(t)ide analogs (NAs) is highly effective at suppressing viral replication, covalently closed circular DNA (cccDNA) persists in hepatocytes to sustain chronic infection, underscoring the need for better interventions and combination therapies. The durable suppression of viral replication and restoration of immune responses through long-acting (LA) therapies offer a promising strategy for sustained HBV control. We transformed tizoxanide (TIZ), a broad-spectrum anti-infective and immunomodulatory agent, into a LA lipophilic prodrug formulation (NM2TIZ) for intramuscular or subcutaneous administration. NM2TIZ exhibited long-term stability during storage and was evaluated in AAV-HBV mice using monotherapy and combination therapy approaches with an LA tenofovir prodrug formulation (NM5TFV). NM5TFV reduced the HBV DNA levels by >2 log₁₀ fold. Furthermore, coadministration of NM5TFV with M2TIZ reduced the expression of liver inflammasomes and profibrotic markers. The NM5TFV and NM2TIZ combination reduced HBV replication, inflammation, and fibrogenesis in AAV-HBV-transduced mice. Full article

Stop codon readthrough is a noncanonical translation strategy employed by certain RNA viruses, in which a viral termination codon is either decoded by host near-cognate tRNAs or canonically recognized by the class I release factor (RF, eRF1 in eukaryotes). Ribosomal A-site competition between near-cognate tRNAs and eRF can shift decoding toward near-cognate tRNAs, thereby promoting non-canonical decoding events by transiently pausing termination and favoring readthrough. This review focuses on two viral cis-elements that modulate readthrough across four viral genera in which this decoding event has been experimentally validated: (i) primary sequences surrounding the stop codon (stop codon context), and (ii) downstream RNA structures. Effects of stop codon context have been observed more broadly in cellular genes, including nonsense suppression in bacteria, with mechanisms including inefficient RF association or tRNA interactions at adjacent sense codons. In eukaryotic systems, interactions with the ribosomal mRNA entry channel have been suggested. Diverse downstream structures, including gammaretroviral pseudoknots and specific structures in alpha- and coltiviruses, further stimulate readthrough in a location- and structure-sensitive manner. This effect has not been consistently observed in chikungunya and triatoviral structures, suggesting a strong dependence on local sequence and structural context. Compared with the larger number of cellular readthrough occurrences that can be detected at low efficiency by ribosome profiling, viral readthrough in mammalian systems is consistently high (>2%). Understanding the interplay between viral RNA elements and host translational machinery, including potential kinetic trapping at the termination codon, provides insights into this unusual elongation mechanism. These findings may have implications for antiviral strategies targeting these RNA elements. Full article

Jing Guan Fang (JGF) is a traditional multi-herb formula used for hyperinflammatory conditions associated with severe viral infections; however, its protein-level effects in macrophage-mediated inflammation remain incompletely characterised. In this study, we combined ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS)-based phytochemical profiling, functional anti-inflammatory assays, and discovery-level proteomic and secretome analyses to investigate the anti-inflammatory effects of JGF in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Phytochemical profiling revealed predominantly flavonoid- and phenolic-related annotated features, together with selected terpenoid- and alkaloid-related annotations. Functionally, JGF treatment was associated with reduced nitric oxide production and differential effects on pro-inflammatory cytokine release, with a clearer concentration-dependent reduction in interleukin-6 (IL-6) and a more variable tumour necrosis factor-α (TNF-α) response, without reducing cell viability. Label-free quantitative proteomics suggested that JGF treatment was associated with modulation of LPS-induced protein changes, including reduced abundance of inflammation-associated proteins such as myristoylated alanine-rich C-kinase substrate (MARCKS) and inducible nitric oxide synthase (NOS2), together with partial restoration of selected regulatory proteins such as AIMP1 and AIMP2. Secretome analysis further suggested that JGF reduced extracellular inflammatory and tissue-remodelling-related mediators, including SERPINE1/PAI-1. Exploratory pathway analysis indicated that JGF treatment was associated with changes in inflammation-related and oxidative stress-related signalling networks. Collectively, these findings provide discovery-level molecular insights into the anti-inflammatory effects of JGF in LPS-stimulated macrophages and support further targeted validation of its pharmacological activity as a candidate multi-component anti-inflammatory formula. Full article

Background: Tenofovir alafenamide (TAF) and entecavir (ETV) are recommended alternatives to tenofovir disoproxil fumarate (TDF) for patients with chronic hepatitis B (CHB) at increased risk of kidney injury. However, data from direct head-to-head comparisons of their long-term renal safety and antiviral efficacy after switching from TDF are lacking. We aimed to compare these outcomes between TAF and ETV. Methods: This multicenter retrospective cohort study included consecutive CHB patients who switched from TDF to either TAF or ETV between January 2012 and December 2021. Inverse probability of treatment weighting using the propensity score was applied to balance the baseline characteristics. Changes in estimated glomerular filtration rate (eGFR) were assessed using a linear mixed-effects model. Renal dysfunction was defined as a decline of at least one GFR category. Results: A total of 235 patients were included (TAF, n = 168; ETV, n = 67). After adjustment for key risk factors, the mean eGFR decline over 36 months was not significantly different between the TAF and ETV groups (−3.21 mL/min/1.73 m² [95% CI, −4.98 to −1.44] vs. −3.49 mL/min/1.73 m² [95% CI, −9.49 to −2.50]; p = 0.856). The 3-year cumulative incidence of renal dysfunction was also not significantly different between groups (16.6% [95% CI, 10.5–23.3] vs. 7.8% [95% CI, 2.7–16.2]; p = 0.135). Alanine aminotransferase normalization rates (83.0% vs. 78.8%; p = 0.575) and virological suppression rates (97.8% vs. 97.1%; p = 1.000) were similarly high in both groups. Conclusions: TAF and ETV demonstrated similar long-term renal safety and antiviral efficacy, supporting both agents as reasonable switch options for CHB patients requiring TDF discontinuation because of renal safety concerns. Full article

The red-spotted grouper nervous necrosis virus (RGNNV) exhibits high pathogenicity in larval C. sonnerati, yet the immune molecular mechanism remains unclear. Non-coding RNAs (ncRNAs) are vital in the host’s immune responses during viral infection. However, there has been no study on ncRNA research for this species to date. We systematically identified 105 DE microRNAs (miRNAs), 157 DE long non-coding RNAs (lncRNAs) and 31 DE circular RNAs between the infection group and control group. Functional enrichment analysis revealed that these differentially expressed genes were significantly enriched in pathways associated with innate immune defense, inflammatory, and cell death, such as JAK-STAT signaling pathway, NF-κB signaling pathway, apoptosis, and necroptosis. Furthermore, the lncRNA–miRNA–mRNA interaction network involving miR-93 was constructed, which may represent a promising candidate therapy target for future investigations. This study presents the first comprehensive ncRNA transcriptome dataset of C. sonnerati infected with RGNNV, identifies key antiviral defense and cell death-related genes and hub pathways, and thereby identifies miR-93-involved lncRNA–miRNA–mRNA network and key targeted genes (STAT1, TRIM25, UNC93B, IL12RB1, IRF8, CDKN1A, FCGR1A) as hub molecular regulators in immune response of this species. Full article

Background: Elranatamab, a bispecific antibody targeting BCMA and CD3, has demonstrated clinical activity in relapsed/refractory multiple myeloma. Real-world evidence regarding infectious complications and supportive care remains limited. We evaluated the early clinical activity, safety profile, infectious complications, and supportive care practices associated with relapsed/refractory multiple myeloma (RRMM). This study represents one of the first multicenter real-world evaluations of elranatamab in Türkiye. Methods: This multicenter retrospective study included 87 patients with relapsed/refractory multiple myeloma treated with elranatamab. Clinical characteristics, treatment responses, immune-mediated toxicities, infectious complications, and supportive care practices were assessed. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. Multivariable analyses were performed to identify factors associated with treatment response and clinical outcomes. Results: At 3 months, ORR was 47.1% in the ITT population, 54.7% in the mITT population, and 83.7% among evaluable patients; corresponding 6-month ORRs were 31.0%, 42.2%, and 81.8%, respectively. The high proportion of patients without landmark response assessments primarily reflected insufficient follow-up, early death, or disease progression. Elevated LDH remained independently associated with lower response probability and inferior clinical outcomes. Cytokine release syndrome (CRS) occurred in 69% of patients, with grade ≥ 3 events in 5.7%, whereas immune effector cell-associated neurotoxicity syndrome (ICANS) was infrequent (4.6%) and no grade ≥ 3 events occurred. Grade ≥ 3 infections occurred in 39% of patients, including CMV events requiring antiviral treatment in 24.1%. No HBV reactivation occurred among patients receiving antiviral prophylaxis. Median PFS and OS were 8.1 and 10.6 months, respectively. Conclusions: Elranatamab demonstrated early clinical activity and a manageable safety profile in a heavily pretreated real-world RRMM population. Infectious complications, including CMV events, remained clinically relevant, emphasizing the importance of supportive care. Longer follow-up is needed to characterize long-term outcomes. Full article