Search Results (76)

Transposable elements (TEs) are increasingly recognized as modulators of innate immunity, yet their antiviral functions remain poorly understood outside mammals and dipterans. Here, we identify a long terminal repeat retrotransposon, LmGypsy, as a key regulator of antiviral defense in Locusta migratoria. The infection of Acrididae reovirus (ARV) induces rapid upregulation of LmGypsy, and its inhibition compromises antiviral resistance. Mechanistically, LmGypsy promotes viral-derived DNA (vDNA) production, which drives Dicer-2-dependent biogenesis of virus-derived small interfering RNAs (vsiRNAs) to enhance RNA interference-mediated viral clearance. Notably, vDNA persists throughout infection, suggesting a role in sustaining antiviral responses. In parallel, LmGypsy activity is positively associated with induction of cyclic GMP-AMP synthase (cGAS)-like receptors (LmcGAS1/2/4) and their downstream effector Stimulator of Interferon Genes (STING). Together, these findings support a dual-layer antiviral strategy and indicate that TE-mediated immunity represents a widespread antiviral mechanism across taxa. Full article

Hyperbranched poly(β-amino ester) (HPAE) is identified as a unique non-viral carrier capable of sustaining high-efficiency transfection under elevated plasmid concentrations, overcoming the aggregation and toxicity limitations of conventional lipid and PEI reagents. We demonstrate that transfection enhancement is driven by concentration-dependent synergism between membrane accumulation and endosomal escape. Guided by this mechanism, a half-volume transfection strategy was established to transiently elevate plasmid concentration without compromising cell viability, enabling superior lentivirus yield and purity. These findings define plasmid concentration as a previously overlooked regulatory axis in nanoparticle-mediated gene delivery and position HPAE as a high-performance platform for scalable therapeutic vector production. Full article

Phloem-restricted poleroviruses cause substantial yield losses in crops. Co-infection of the polerovirus brassica yellows virus (BrYV) with the umbravirus pea enation mosaic virus 2 (PEMV 2) results in synergistic interactions that enable BrYV to overcome phloem limitation in Nicotiana benthamiana, yet the associated host transcriptional responses remain poorly understood. At 7 days post inoculation (dpi), BrYV RNA accumulation was increased in plants co-infected with BrYV and PEMV 2, although no visible symptoms or detectable cell death were observed. By 14 dpi, extensive cell death was induced in upper leaves infected with BrYV and PEMV 2. Transcriptome analysis at 14 dpi identified 45, 188, and 1962 differentially expressed genes (DEGs) in leaves infected with BrYV, PEMV 2, and co-infected with BrYV and PEMV 2, respectively, compared with mock-inoculated plants. A large number of DEGs, Gene Ontology terms, and KEGG pathways were predominantly observed in co-infected plants. Notably, expression changes were observed in genes related to plasmodesmata-associated processes, RNA silencing, photosynthesis, cell death, and ethylene biosynthesis and signaling during co-infection. These results provide a transcriptome-based overview of host responses during the late stage of BrYV and PEMV 2 co-infection and highlight the complexity of viral synergism between phloem-limited and taxonomically distinct plant viruses. Full article

Non-AIDS-defining cancers (NADCs) have emerged as an increasingly prominent cause of non-AIDS-related morbidity and mortality among people living with HIV (PLWH). However, the scarcity of NADC clinical samples, compounded by privacy and security constraints, continues to present formidable obstacles to advancing pathological and clinical investigations. In this study, we adopted a joint analysis strategy and deeply integrated and analyzed transcriptomic data from 12,486 PLWH and cancer patients to systematically identify potential key regulators for 23 NADCs. This effort culminated in NADCdb—a database specifically engineered for NADC pathological exploration, structured around three mechanistic frameworks rooted in the interplay of immunosuppression, chronic inflammation, carcinogenic viral infections, and HIV-derived oncogenic pathways. The “rNADC” module performed risk assessment by prioritizing genes with aberrant expression trajectories, deploying bidirectional stepwise regression coupled with logistic modeling to stratify the risks for 21 NADCs. The “dNADC” module, synergized patients’ dysregulated genes with their regulatory networks, using Random Forest (RF) and Conditional Inference Trees (CITs) to identify pathogenic drivers of NADCs, with an accuracy exceeding 75% (in the external validation cohort, the prediction accuracy of the HIV-associated clear cell renal cell carcinoma model exceeded 90%). Meanwhile, “iPredict” identified 1905 key immune biomarkers for 16 NADCs based on the distinct immune statuses of patients. Importantly, we conducted multi-dimensional profiling of these key determinants, including in-depth functional annotations, phenotype correlations, protein–protein interaction (PPI) networks, TF-miRNA-target regulatory networks, and drug prediction, to deeply dissect their mechanistic roles in NADC pathogenesis. In summary, NADCdb serves as a novel, centralized resource that integrates data and provides analytical frameworks, offering fresh perspectives and a valuable platform for the scientific exploration of NADCs. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. It usually arises in cirrhotic liver, where chronic inflammation and fibrosis create a tumor-permissive microenvironment. Dysregulation of microRNAs (miRNAs), particularly upregulation of the oncomiR miR-221 and loss of the tumor suppressor miR-199a-3p represent key drivers of liver carcinogenesis. The TG221 transgenic mouse, designed to overexpress miR-221 in hepatocytes, provides a relevant in vivo platform for mechanistic studies and for testing preventive and therapeutic approaches. The TG221 model recapitulates miR-221-driven tumorigenesis, including suppression of p27, p57 and Bmf. It is characterized by steatohepatitic injury and accelerated tumor formation after genotoxic challenge. In the cirrhotic CCl₄-induced background, TG221 mice develop fibrosis and cirrhosis followed by dysplastic and malignant lesions, mirroring the natural history of human HCC. Metformin administered during early fibrosis prevented macroscopic tumor formation and suppressed PI3K/AKT/mTOR signaling. Anti-miR-221 and miR-199a-3p mimics reduced tumor burden, restored tumor-suppressive pathways and improved liver integrity, thus indicating feasible chemopreventive strategies. From a therapeutic point of view, miR-199a-3p replacement synergized with palbociclib and overcame sorafenib resistance. A miR-199a-3p-responsive oncolytic adenovirus achieved tumor-selective replication with minimal toxicity. This review highlights the importance of the TG221 transgenic mouse as a powerful model for studying miRNA-driven hepatocarcinogenesis and enables preclinical evaluation of RNA-based chemopreventive and therapeutic approaches. Metformin, miRNA inhibition, miRNA replacement and miRNA-guided viral therapies emerge as promising approaches for advancing precision prevention and treatment strategies in HCC. Full article

The H3N8 low pathogenic avian influenza virus (LPAIV) exhibits broad host tropism, infecting diverse avian and mammalian species, raising concerns about its zoonotic potential. Following the emergence of human infections with H3N8 LPAIV in China, including a fatal case, we investigated the epidemiological and virological characteristics of this virus in Guangdong Province. In 2022, a serological survey revealed H3N8 seroprevalence rates of 10.85% in farmed chickens and 7.97% in ducks. We isolated three H3N8 viruses, designated as A/chicken/Qingyuan/22/2022 (H3N8); A/chicken/Qingyuan/31/2022 (H3N8); and A/chicken/Qingyuan/15/2022 (H3N8), and found that these chicken isolates, like the human isolate A/Changsha/1000/2022, share the same E190 residue. This residue can synergize with sites such as Q226 and G228 to enhance binding affinity for SAα-2,6-Gal. Additionally, they harbor the three amino acid residues N193, W222, and S227. Among these, N193 has the potential to form hydrogen bonds with α2-6-linked glycans, while W222 and S227 may alter the conformational flexibility of the 220-loop. These two effects collectively endow the H3N8 isolates with dual receptor-binding properties. These findings suggest a shift in receptor specificity, potentially facilitating viral adaptation to mammalian hosts. Characterization of viral genome detection dynamics, and histopathology in animal models further elucidated the viral infection dynamics. Our study provides critical insights into the evolutionary trajectory and zoonotic potential of the H3N8 LPAIV. Full article

Background/Objectives: Colorectal cancer (CRC) is the third most common cancer and a leading cause of death worldwide. Identifying non-invasive, early indicators of CRC risk remains essential and could help reduce its health burden. Excess adiposity and chronic inflammation are major predisposing factors for precancerous adenomatous polyposis (AP) and CRC, while diet- or surgery-induced weight loss was associated with a reduced risk. Viral infections also represent cancer risk factors through direct or synergic mechanisms, though no definitive causal link has been established for CRC. Moreover, interest is growing on the role of oral viruses as predictors of disease. Methods: In this study, highly sensitive and specific Luminex-based screening assays were used to perform a comprehensive characterization of oral infections by Human Herpes (HHV), Polyoma (HPyV) and Papilloma (HPV) Viruses in CRC patients (N = 50), healthy controls (N = 46; normal weight, NW = 26; overweight, OW = 20), and high-risk individuals with obesity (N = 35) or adenomatous polyposis (AP, N = 22). Results: We observed increased HPyV prevalence in AP, and higher single and multiple β-HPV infection rates in AP and CRC compared to controls. A panel of β-HPV genotypes, including oncogenic HPV5, was overrepresented in CRC and high-risk groups, and some of them showed an association with the male sex. The prevalence of most infections decreased in the obese cohort following bariatric surgery, alongside weight loss and reduction of inflammatory markers. Furthermore, oral infections by viral types previously detected in CRC tissue and adjacent mucosa also declined after surgery. Conclusions: Altogether, these findings suggested a role for oral β-HPV types as potential sex- and lifestyle-related, modifiable indicators of cancer risk. Full article

Background: Studies have suggested a synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a key target and master transcriptional factor regulating myeloma cell survival. Method: A 3 + 3 phase I trial was conducted to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least one prior line of therapy. Three dose levels (DLs) were planned. The cycle length was 28 days. IBR was administered orally daily in doses of 560 mg on DL1-2 and 840 mg on DL3, LEN was administered orally on days 1–21 in doses of 15 mg on DL1 and 25 mg on DL2-3, and DEX was administered orally on days 1, 8, 15, and 22 in a dose of 40 mg if age < 75 years or in a dose of 20 mg if it was ≥75 years for DL1-3. Patients with a glomerular filtration rate (GFR) <60 but ≥30 mL/min were treated in accordance with the manufacturer’s instructions with LEN 10 mg. Dose-limiting toxicities (DLTs) included the following: grade 4 neutropenia lasting more than 5 days, thrombocytopenia, febrile neutropenia, nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; and grade 3–4 hyperglycemia or a thrombotic/embolic event, and other nonhematologic toxicities. The overall response rate (ORR) was defined as the percentage of patients with a partial response (PR), very good partial response (VGPR), or complete response (CR) according to IMWG criteria on two consecutive evaluations at least 4 weeks apart. The clinical benefit rate (CBR) was defined as the percentage of patients with stable disease (SD) or a better outcome on two consecutive evaluations at weeks apart. Results: Fourteen patients (DL1: six patients; DL2: three patients; DL3: five patients) were registered for the study from March 2019 to May 2023, prior to its closure due to limited accrual. Thirteen patients are included in the summary of toxicities and response as one patient on DL3 halted participation prior to the start of the treatment. Two patients on DL3 were excluded from the determination of MTD: one having discontinued cycle 1 treatment due to COVID-19 infection and the another having mistakenly taken 280 mg/day of IBR instead of the assigned 840 mg/day dose during cycle 1. Only one patient developed a DLT, on DL1 with grade 3 non-viral hepatitis. The median number of cycles administered was 4 (range: 1–56). Severe toxicities reported included grade 4 lymphocytopenia (1), grade 4 thrombocytopenia (1), and grade 5 sepsis in the setting of PD (1). Disease responses included a VGPR on DL1 and CR on DL3. Thus, the ORR was 15.4% (90% CI: 2.8–41.0%). One patient on DL1 maintained SD for 4.6 years before discontinuing the treatment to undergo an alternative therapy. Another five patients maintained SD for ≥ 2 consecutive cycles. Thus, the CBR was 61.5% (90% CI: 35.5–83.4%). Conclusions: The combination of LEN with IBR in RR MM proved feasible, with manageable toxicities and the majority of discontinuations being due to disease progression. Full article

Galectin-3 (Gal-3) is a β-galactoside-binding lectin that mediates diverse signaling events in multiple cell types, including immune cells. It is also a prognostic indicator for multiple clinically important disorders, including cardiovascular disease. Gal-3 binds to cell surface glycans to form lattices that modulate surface receptor signaling and internalization. However, the tissue-specific regulation of Gal-3 surface expression remains poorly understood. Here, we review evidence for the involvement of Gal-3 in cell surface signaling, intranuclear events, and intracellular trafficking. Our focus will be on the O-GlcNAc modification as a regulator of Gal-3 biosynthesis, non-canonical secretion, and recycling. We argue that the nutrient-driven cytoplasmic hexosamine biosynthetic pathway (HBP) and endomembrane transport mechanisms generate unique pools of nucleotide sugars. The differing levels of nucleotide sugars in the cytosol, endoplasmic reticulum (ER), and Golgi apparatus generate differential thresholds for the responsiveness of O-GlcNAc cycling, N- and O-linked glycan synthesis/branching, and glycolipid synthesis. By regulating Gal-3 synthesis and non-canonical secretion, O-GlcNAc cycling may serve as a nexus constraining Gal-3 cell surface expression and lattice formation. This homeostatic feedback mechanism would be critical under conditions where extensive glycan synthesis and branching in the endomembrane system and on the cell surface are maintained by elevated hexosamine synthesis. Thus, O-GlcNAc cycling and Gal-3 synergize to regulate Gal-3 secretion and influence cellular signaling. In humans, Gal-3 serves as an early-stage prognostic indicator for heart disease, kidney disease, viral infection, autoimmune disease, and neurodegenerative disorders. Since O-GlcNAc cycling has also been linked to these pathologic states, exploring the interconnections between O-GlcNAc cycling and Gal-3 expression and synthesis is likely to emerge as an exciting area of research. Full article

Bovine viral diarrhoea virus (BVDV) is the causative agent of bovine viral diarrhoea/mucocutaneous disease (BVD-MD). Its associated co-infections pose a threat to the cattle industry, which is becoming a key breakthrough in the global system of prevention in the cattle industry. In recent years, cases of co-infection have occurred and been reported from time to time, and this situation not only poses certain difficulties in controlling the outbreak and in treatment in the farming industry, but also poses considerable challenges in detection and diagnosis. In this review, by systematically integrating studies on BVDV co-infection, we firstly compared and analysed the characteristics of BVDV co-infection with viruses, bacteria and other pathogens in in vivo/in vitro models in terms of synergism, host immune response and epidemiological transmission. Then we systematically constructed a BVDV Co-infection Impact Map, which demonstrates a paradigm of pathogen–host–immune interactions in the transmission of BVDV and provides a theoretical framework for breaking through the current precision diagnostic strategies and showcasing the effectiveness of integrated prevention and control. Full article

Viral diseases are a frequent problem in the agricultural sector, causing significant economic losses, so their management is a constant challenge for producers and researchers. One of the factors that often complicates the control of viral diseases in plants is mixed infections, which occur when two or more viruses are present in a plant, generating a complex expression of symptoms. During a mixed infection, the following types of interactions basically occur: complementation and interference, the effect of which produces synergism, antagonism, or no effect. However, there are also subcategories of effects. This makes early detection difficult, and this infection can also give a competitive advantage to the pathogens involved. This review presents updated information on mixed viral infections in plants, the interaction categories, the severity of symptoms, and the impact on plants and vectors. The intention is to share information to better understand the etiology of the diseases. Full article

Viral infections remain a major concern, as existing treatments often yield inadequate responses or lead to the development of antiviral resistance in some cases. Fucoidan extracted from Undaria pinnatifida (F) is a natural sulphated polysaccharide that exhibits antiviral action. Despite its potential, the biomedical application of F is limited due to its difficult administration through trans-mucosal, skin, or oral ingestion. The most effective way to solve these problems is to propose novel methods of administration aiming to ensure better contact between the biopolymers and pathogens, leading to their inactivation. In this work, the synthesis of films based on chitosan (Ch)-coupled F is reported, aiming to generate a synergic effect between both biopolymers in terms of their antiviral and antioxidant capability. Biocomposites were prepared by a sonochemical method. They were characterized to infer structural properties, functionality, and possible F-Ch interactions by using Zeta potential, FTIR, and XRD techniques. The biocomposites showed excellent film-forming ability. They also exhibited improved antioxidant activity with respect to F and Ch individually and proved to be non-cytotoxic. These results demonstrate, for the first time, the antiviral activity of F:Ch biocomposites against bovine coronavirus and human viruses (adenovirus, poliovirus, herpes simplex, and respiratory syncytial virus), which could be applied in film form to prevent or treat viral infections. Full article

This study explores the effects of plant compounds on human papillomavirus (HPV)-induced W12 cervical precancer cells and bioelectric signaling. The aim is to identify effective phytochemicals, both individually and in combination, that can prevent and treat HPV infection and HPV associated cervical cancer. Phytochemicals were tested using growth inhibition, combination, gene expression, RT PCR, and molecular docking assays. W12 cells, derived from a cervical precancerous lesion, contain either episomal or integrated HPV16 DNA. Several compounds, including digoxin, tanshinone IIA, dihydromethysticin and carrageenan, as well as fractions of turmeric, ginger and pomegranate inhibited the growth of W12 precancer and cervical cancer cells. Curcumin and tanshinone IIA were the most active and relatively nontoxic compounds. RT-PCR analysis showed that tanshinone IIA activated the expression of p53, while repressing the expression of HPV16 E1, E2, E4, E6, and E7 viral transcripts in W12 (type 1 and 2) integrant cells. In addition, curcumin synergized with tanshinone IIA in HeLa cells. Molecular docking studies suggested tanshinone IIA and curcumin bind to the Na⁺/K⁺-ATPase ion channel, with curcumin binding with higher affinity. Our findings highlight the potential of these multifaceted phytochemicals to prevent and treat HPV-induced cervical cancer, offering a promising approach for combinatorial therapeutic intervention. Full article

Human adenovirus (HAdV)-based oncolytic vectors, which are designed to preferentially replicate in and kill cancer cells, have shown modest efficacy in human clinical trials in part due to poor viral distribution throughout the tumor mass. Previously, we showed that expression of the p14 fusion-associated small transmembrane (FAST) fusogenic protein could enhance oncolytic HAdV efficacy and reduce tumor growth rate in a human xenograft mouse model of cancer. We now explore whether co-expression of the adenovirus death protein (ADP) with p14 FAST protein could synergize to further enhance oncolytic vector efficacy. ADP is naturally encoded within the early region 3 (E3) of HAdV, a region which is frequently removed from HAdV-based vectors, and functions to enhance cell lysis and progeny release. We evaluated a variety of approaches to achieve optimal expression of the two proteins, the most efficient method being insertion of an expression cassette within the E3 deletion, consisting of the coding sequences for p14 FAST protein and ADP separated by a self-cleaving peptide derived from the porcine teschovirus-1 (P2A). However, the quantities of p14 FAST protein and ADP produced from this vector were reduced approximately 10-fold compared to a similar vector-expressing only p14 FAST protein and wildtype HAdV, respectively. Compared to our original oncolytic vector-expressing p14 FAST protein alone, reduced expression of p14 FAST protein and ADP from the P2A construct reduced cell-cell fusion, vector spread, and cell-killing activity in human A549 adenocarcinoma cells in culture. These studies show that a self-cleaving peptide can be used to express two different transgenes in an armed oncolytic HAdV vector, but also highlight the challenges in maintaining adequate transgene expression when modifying vector design. Full article

The latent viral reservoir represents one of the major barriers to curing HIV-1. Focus on the “kick and kill” (also called “shock and kill”) approach, in which virus expression is reactivated, and then cells producing virus are selectively depleted, has led to the discovery of many latency-reversing agents (LRAs) that have furthered our understanding of the mechanisms driving HIV-1 latency and latency reversal. Thus far, individual compounds have yet to be robust enough to work as a therapy, highlighting the importance of identifying new compounds that target novel pathways and synergize with known LRAs. In this study, we identified a promising LRA, NSC95397, from a screen of ~4250 compounds. We validated that NSC95397 reactivates latent viral transcription and protein expression from cells with unique integration events and across different latency models. Co-treating cells with NSC95397 and known LRAs demonstrated that NSC95397 synergizes with different drugs under both standard normoxic and physiological hypoxic conditions. NSC95397 does not globally increase open chromatin, and bulk RNA sequencing revealed that NSC95397 does not greatly increase cellular transcription. Instead, NSC95397 downregulates pathways key to metabolism, cell growth, and DNA repair—highlighting the potential of these pathways in regulating HIV-1 latency. Overall, we identified NSC95397 as a novel LRA that does not largely alter global transcription, shows potential for synergy with known LRAs, and may act through novel pathways not previously recognized for their ability to modulate HIV-1 latency. Full article