Search Results (3,642)

Arboviruses such as dengue (DENV), Zika (ZIKV), and chikungunya (CHIKV) remain major global health threats, especially in tropical regions, with no effective antiviral treatments available. Recent research highlights progress in identifying antiviral compounds from natural sources against arboviruses belonging to the flavivirus genus, such as DENV and ZIKV. These compounds, derived from plants, marine organisms, and microorganisms, fall into several key chemical classes: quinones, flavonoids, phenolics, terpenoids, and alkaloids. Quinones inhibit viral entry and replication by targeting envelope proteins and proteases. Flavonoids disrupt RNA synthesis and show virucidal activity. Phenolic compounds reduce expression of non-structural proteins and inhibit enzyme function. Terpenoids demonstrate broad-spectrum activity against multiple arboviruses, while alkaloids interfere with early infection stages or viral enzymes. To support the reviewed literature, we performed molecular docking analyses of selected natural compounds and some arboviral proteins included as illustrative examples. These analyses support the structure–activity relationships reported for some natural compounds and highlight their potential interactions with essential viral targets such as the NS2B-NS3 protease and NS5 polymerase. Together, these literature and computational insights highlight the potential of natural products as scaffolds for antiviral drug development. Full article

Ribonucleic acid (RNA) polymerases are macromolecular machines that catalyze the synthesis of RNA macromolecules, the sequences of which are coded for by the sequences of regions of deoxyribonucleic acid (DNA) macromolecules in the nucleus of eukaryotic cells, or nuclei in the case of many mature striated muscle cells, or myocytes, which are in many cases polynucleated. Herein, we review the evidence that transcription, the activity of RNA polymerases that is an essential step in gene expression, and processes related to maturation of eukaryotic RNA can be influenced by the macromolecule actin and its macromolecular complex of filamentous actin and its association with actin-binding proteins in the nucleus. We furthermore hypothesize that the macromolecular complexes of troponin (Tn) and tropomyosin (Tm), which bind actin filaments in the cytoplasm of striated muscle myocytes to form thin filaments and which are also found in the nuclei of striated muscle myocytes and some cancerous cells, could modulate that influence of nuclear actin on transcription when present in a nucleus. Interestingly, troponin and tropomyosin could confer Ca²⁺ dependence to transcriptional modulation by nuclear actin, a mechanism that would complement Ca²⁺-dependent modulation of post-translational modifications that influence gene expression. Full article

Objective: Previous reports showed that periodontopathic bacteria induce epithelial–mesenchymal transition (EMT) in oral squamous cell carcinoma (OSCC). Fisetin, a foodborne flavonoid, is reportedly associated with anticancer potential in various carcinogenic processes. This study aimed to elucidate the effects of fisetin on Fusobacterium nucleatum- and Porphyromonas gingivalis-induced EMT in OSCC cells. Methods: OSCC cells were co-cultured with live and heat-killed forms of F. nucleatum and P. gingivalis. The concentration of fisetin was set at 10 μM. Morphological changes in the OSCC cells were observed under a light microscope. Cell viability was measured using the Cell Counting Kit-8 assay, whereas migration was examined via wound healing. The mRNA expression of EMT-related markers was quantified using quantitative real-time polymerase chain reaction (PCR), and the expression of EMT-related markers and Wnt pathway-associated proteins was examined via Western blotting. Results: At a multiplicity of infection (MOI) of 300:1 for F. nucleatum and 100:1 for P. gingivalis, OSCC cell viability remained unchanged; however, wound closure rates increased significantly relative to the control. Likewise, treatment with fisetin (10 µM) did not materially alter viability; nevertheless, it attenuated promigratory effects induced by heat-killed periodontal pathogens at 3 h and 6 h. The OSCC cells exhibited EMT-like morphological changes after 6 h of co-culture with heat-killed pathogens. Consistently, reverse-transcriptase quantitative PCR and Western blot analyses showed increased expression of TWIST, ZEB1, and N-cadherin, accompanied by decreased E-cadherin expression, which was more pronounced in F. nucleatum than in P. gingivalis. However, fisetin reversed these trends. Moreover, co-culture with heat-killed pathogens markedly elevated β-catenin protein levels. In line with modulation of canonical Wnt/β-catenin signaling, fisetin and a Wnt inhibitor reduced β-catenin expression, whereas co-treatment with a Wnt agonist restored β-catenin levels in the presence of fisetin. Conclusions: Heat-killed F. nucleatum and P. gingivalis induced EMT in OSCC cells, with F. nucleatum exerting the strongest effect. Fisetin suppressed pathogen-driven EMT, at least partly via canonical Wnt/β-catenin signaling, highlighting its potential therapeutic value and warranting further investigation. Full article

Background/Objectives: Molnupiravir (MOV) and nirmatrelvir (NMV) are antiviral drugs that were FDA-approved under the emergency use authorization (EUA) for coronavirus disease-2019 (COVID-19) treatment. MOV and NMV target the viral RNA-dependent RNA polymerase and main protease, respectively. Paxlovid is a combination of NMV and ritonavir (RTV), an inhibitor of the human cytochrome P450-3A4 (hCYP3A4). In this study, the structural consequences in the hCYP3A4 caused by MOV-induced mutations (MIM) were evaluated using in silico tools. Methods: MOV-induced mutations (MIM) were inserted into all the possible hotspots in the active site region of the hCYP3A4 gene, and mutant protein models were built. Structural changes in the heme-porphyrin ring of hCYP3A4 were analyzed in the presence and absence of substrates/inhibitors, including RTV. Molecular dynamics (MD) simulations were performed to analyze the effect of MIM-induced structural changes in hCYP3A4 on drug binding. Results: MD simulations confirm that MIMs, R375G and R440G in hCYP3A4 severely affect the heme-porphyrin ring stability by causing a tilt that in turn affects RTV binding, suggesting a possible inefficiency in the function of hCYP3A4. Similar results were seen for amlodipine, atorvastatin, sildenafil and warfarin, which are substrates of hCYP3A4. Conclusions: The current in silico studies indicate that hCYP3A4 containing MIMs can create complications in the treatment of COVID-19 patients, particularly with co-morbidities due to its functional inefficiency. Hence, clinicians must be vigilant when using MOV in combination with other drugs. Further in vitro studies focused on hCYP3A4 containing MIMs are currently in progress to support our current in silico findings. Full article

Sulfoxaflor, an insecticide, acts on nicotinic acetylcholine receptors. It has a functional group similar to that of neonicotinoid insecticides, which are testicular toxicants. Recently, the adverse effects of sulfoxaflor on the testes have been reported in rats. This study aimed to address the lack of reports on sulfoxaflor administration in mice and its effects on the testes. ICR mice (3- and 10-week-old) were treated ad libitum with two different concentrations (10 and 100 mg/kg) of sulfoxaflor for 4 and 8 weeks. Histological analysis and real-time reverse transcription polymerase chain reaction were performed. Testis weights relative to body weights in the sulfoxaflor groups showed no significant difference compared to the control group. Testicular tissue in the sulfoxaflor groups was unchanged compared to that in the control group. The sulfoxaflor-treated group showed no significant differences in the mRNA expression of luteinizing hormone and follicle-stimulating hormone in the pituitary gland compared to the control group. Furthermore, no significant differences were noted in the mRNA expression levels of various gene markers in the testes between the sulfoxaflor-treated and control groups. These markers include those related to Leydig cells, testosterone synthesis, Sertoli cells, proliferating cells, meiotic cells, pachytene spermatocytes, round spermatids, apoptotic cells, antioxidant enzymes, oxidative stress factors, and mitochondrial function. In contrast to findings in rats, which showed testicular toxicity, sulfoxaflor administration at low concentrations did not adversely affect intratesticular cells in either mature or immature mice at the doses and time points examined. In the future, we would like to conduct research on high concentrations of sulfoxaflor by changing the administration method. Full article

Calcific aortic valve disease (CAVD) is characterized by progressive valve remodeling and calcification. Moreover, microRNAs (miRNAs) are emerging as key regulators of cardiovascular pathology and potential circulating biomarkers. We performed high-throughput miRNA profiling in calcified aortic valve tissue and matched patient serum samples using an array that included 98 human miRNAs. Expression data were log10-transformed and filtered to identify biologically relevant miRNAs. Shared miRNAs between tissue and serum were further validated by quantitative real-time polymerase chain reaction (qRT-PCR) in patients and healthy controls. Of the 49 actively expressed miRNAs, 18 were shared between valve tissue and serum. Thus, qRT-PCR validation revealed significant downregulation of miR-17-5p and miR-29a-3p in CAVD patient serum compared to controls. These results indicate that disease-associated miRNA alterations in calcified valves are mirrored in circulation. miR-17-5p and miR-29a-3p represent promising circulating biomarkers for CAVD, reflecting underlying pathological remodeling and extracellular matrix dysregulation. Our findings provide a framework for non-invasive monitoring of valve calcification and highlight miRNA-mediated pathways as potential therapeutic targets. Full article

Phages play a role in shaping ecosystems by controlling host abundance via cell lysis, driving host evolution via horizontal gene transfer, and promoting nutrient cycling. The genus Bradyrhizobium includes bacteria able to symbiotically nodulate the roots of soybean (Glycine max), providing the plant with a direct source of biologically fixed nitrogen. Optimizing this symbiosis can minimize the use of nitrogen fertilizers and make soybean production more sustainable. Phages targeting Bradyrhizobium may modify their hosts’ genotype, alter phenotypic traits such as symbiotic effectiveness, and mediate competition among strains for nodulation sites. Sixteen phages were isolated against B. diazoefficiens strain USDA110 and B. elkanii strains USDA94 and USDA31. Comparative analyses revealed host species-dependent diversity in morphology, host range, and genome composition, leading to the identification of three previously undescribed phage species. Remarkably, all B. elkanii phages shared a siphophage morphology and formed a single species with >97% nucleotide identity, even when isolated from farms separated by up to ~70 km, suggesting genomic stability across geographic scales. In contrast, phages isolated against B. diazoefficiens had a podophage-like morphology, exhibited greater genetic diversity, and divided into two distinct species. Although no phages were recovered against the B. japonicum strains or native Delaware Bradyrhizobium isolates tested, some Delaware Bradyrhizobium isolates showed susceptibility in a host range assay. The phage genomes demonstrated features predicting phenotypes. The phage terminase genes predicted headful packaging which promotes generalized transduction. The B. elkanii phages all carried tmRNA genes capable of rescuing stalled ribosomes, and all but one of the phages isolated against the two host species carried DNA polymerase A indicating greater phage control of genome replication. State-of-the-art structural annotation of a hypothetical gene shared by the B. diazoefficiens phages, having a mean amino acid identity of ~25% and similarity of ~35%, predicted a putative tail fiber function. Together this work expands the limited knowledge available on soybean Bradyrhizobium phage ecology and genomics. Full article

The picornavirus 3CD protein is a precursor to the 3C main protease and the 3D RNA-dependent RNA polymerase. In addition to its functions in proteolytic processing of the virus polyprotein and cleavage of key host factors, the 3C domain interacts with cis-acting replication elements (CREs) within the viral genome to regulate replication and translation events. We investigated the molecular determinants of RNA binding to 3C using a wide range of biophysical and computational methods. These studies showed that 3C binds to a broad spectrum of RNA oligonucleotides, displaying minimal sequence and structure dependence, at least for these shorter RNAs. However, they also uncovered a novel aspect of these interactions, that is, 3C-RNA binding can induce liquid–liquid phase separation (LLPS), with 3CD–RNA interactions likewise leading to LLPS. This may be a general phenomenon for other 3C and 3C-like proteases and polyproteins incorporating 3C domains. These findings have potential implications in understanding virally induced apoptosis and the control of stress granules, which involve LLPS and include other proteins with known interactions with 3C/3CD. Full article

Nasopharyngeal carcinoma (NPC) is a malignant tumor in which the etiologic contribution of Epstein–Barr virus (EBV) is well established. However, similar to that of oropharyngeal carcinoma, some papers reported that human papilloma virus (HPV) contributed to the development of NPC in non-endemic regions. Previously, we conducted a study on HPV infection in patients with NPC between 1996 and 2015 in our department. The current study aims to evaluate the incidence and role of HPV infection in NPC pathogenesis using samples of NPC after 2015. Paraffin-embedded tumor samples from 26 patients with NPC who were treated at our department between 2015 and 2022 were analyzed. HPV polymerase chain reaction, p16 immunohistochemistry, HPV genotyping, and in situ hybridization for EBV-encoded RNA were performed to determine the viral infection status. Of the 26 patients, 19 (73%) were EBV-positive and HPV-negative, 1 (4%) was EBV-negative and HPV-positive, and 6 (23%) were negative for both EBV and HPV. The detection rate of HPV has slightly increased from 3% to 4% over the past decade. Although Japan is a non-endemic region for NPC, HPV infection is exceedingly rare and may have a limited role in NPC development in Japan. However, the detection rate of HPV has not significantly changed in the past decade, further supporting the view that HPV has a relatively small impact on the pathogenesis of NPC in Japan. Full article

Bacteria are promising sources of bioflocculants, yet their regulatory machinery for bioflocculant synthesis remains underexplored. This study focused on evaluating the biosynthetic genes, optimisation and assessment of bioflocculation efficiency in wastewater. The isolated bioflocculant producers were identified by 16S rRNA and rpoB gene analysis. Polymerase chain reaction was used to assess the presence of polyketide synthase I (PKS-1), polyketide synthase II (PKS-II), non-ribosomal peptide synthetase (NRPS), epsH and epsJ. A one-factor-at-a-time technique was utilised for optimisation of culture conditions. The bioflocculants’ efficiencies were evaluated in wastewater using the Jar test method. Among 31 isolates, Klebsiella michiganensis and Klebsiella pasteurii were the most potent bioflocculant producers. They both revealed the presence of PKS-II. K. pasteurii possessed the epsH gene. The optimal conditions for maximum bioflocculant production (95% activity) by K. michiganensis were a temperature of 35 °C, pH of 5, galactose, tryptophan and 84 h of incubation. K. pasteurii’s maximum bioflocculant production of 83% was obtained at a temperature of 35 °C and pH of 7, with galactose, a mixture of urea, yeast extract, and ammonium sulphate (NH₄)₂SO₄ and 96 h of fermentation. Their bioflocculants reduced the chemical oxygen demand and turbidity of wastewater by more than 70%. The bacteria had promising bioflocculant production with potential applicability in wastewater treatment. Full article

Helper component-proteinase (HC-Pro), encoded by tobacco vein banding mosaic virus (TVBMV), can cause various viral symptoms and even abortion. HC-Pro counteracts host-mediated inhibition by interfering with the accumulation of microRNAs (miRNAs) and small interfering RNAs (siRNAs). However, it is unclear whether the abortion phenotype of transgenic plants expressing HC-Pro is related to the abnormal expression of TEOSINTE BRANCHED 1/CYCLOIDEA/PROLIFERATING cell factors (TCPs), which are involved in regulating fertility. In this study, the molecular mechanisms through which HC-Pro causes various sterile phenotypes in plants were investigated. Reverse transcription–quantitative polymerase chain reaction (RT–qPCR) and Northern blotting revealed that in HC-Pro transgenic plants, the expression levels of TCP4 and TCP24 significantly increased. The increased expression of TCP4 further upregulated LIPOXYGENASE2 (LOX2), a gene encoding a key enzyme in the synthesis of jasmonic acid (JA) precursors. Further studies confirmed that the aberrant expression of TCP3, TCP4 and TCP24 blocks the elongation of petals and anthers and that the aberrant expression of TCP4 and TCP24 blocks the release of pollen. This study demonstrated that HC-Pro affects the expression levels of the miR319-targeted genes TCP2, TCP3, TCP4, TCP10 and TCP24, thereby affecting the normal development of floral organs and resulting in plant abortion. Both tobacco and Arabidopsis thaliana were used as model systems in this study on virus-mediated fertility, which provides important information for understanding how viral pathogenicity affects the regulation of fertility in crops. Full article

This review summarizes the current knowledge on the role of alternative σ factors in the highly invasive spirochaete Leptospira interrogans, the causative agent of leptospirosis. This globally distributed zoonosis affects both animals and humans, resulting in substantial public health and economic consequences. Together with the primary σ⁷⁰, alternative σ factors provide transcriptional flexibility essential for bacterial adaptation to environmental changes and host–pathogen interactions. Comparative genomic analyses have revealed that the L. interrogans genome encodes 14 σ factors, including one housekeeping σ⁷⁰-like factor and three types of alternative σ factors: σ⁵⁴, σ²⁸, and 11 predicted extracytoplasmic function (ECF, σᴱ-type) factors. This review discusses the characteristics of these regulators, with particular emphasis on the poorly understood ECF σ factors and their potential roles in gene regulation, adaptive responses, and pathogenicity. Full article

Human immunodeficiency virus (HIV-1) and SARS-CoV-2 continue to co-burden global health, motivating discovery of broad-spectrum small molecules. Conessine, a steroidal alkaloid, has reported membrane-active and antimicrobial properties but remains underexplored as a dual antiviral chemotype. To interrogate conessine’s multi-target antiviral potential against key enzymatic and entry determinants of HIV-1 and SARS-CoV-2 and to benchmark performance versus approved comparators. Eight targets were modeled: HIV-1 reverse transcriptase (RT, 3V81), protease (PR, 1HVR), integrase (IN, 3LPT), gp120–gp41 trimer (4NCO); and SARS-CoV-2 main protease (M^pro, 6LU7), papain-like protease (PL^pro, 6W9C), RNA-dependent RNA polymerase (RdRp, 7BV2), spike RBD (6M0J). Ligands (conessine; positive controls: dolutegravir for HIV-1, nirmatrelvir for SARS-CoV-2) were prepared with standard protonation, minimized, and docked using AutoDock Vina v 1.2.0exhaustiveness 4; 20 poses). Binding modes were profiled in 2D/3D. Protocol robustness was verified by re-docking co-crystallized ligands (RMSD ≤ 2.0 Å). Atomistic MD (explicit TIP3P, OPLS4, 300 K/1 atm, NPT; 50–100 ns) assessed pose stability (RMSD/RMSF), pocket compaction (Rg, volume), and interaction persistence; MM/GBSA provided qualitative energy decomposition. ADMET was predicted in silico. Conessine showed coherent, hydrophobically anchored binding across both viral panels. Best docking scores (kcal·mol⁻¹) were: HIV-1—PR −6.910, RT −6.672, IN −5.733; SARS-CoV-2—spike RBD −7.025, M^pro −5.745, RdRp −5.737, PL^pro −5.024. Interaction maps were dominated by alkyl/π-alkyl packing to catalytic corridors (e.g., PR Ile50/Val82, RT Tyr181/Val106; M^pro His41/Met49; RBD L455/F486/Y489) with occasional carbon-/water-mediated H-bonds guiding orientation. MD sustained low ligand RMSD (typically ≤1.6–2.2 Å) and damped RMSF at catalytic loops, indicating pocket rigidification; MM/GBSA trends (≈ −30 to −40 kcal·mol⁻¹, dispersion-driven) supported persistent nonpolar stabilization. Benchmarks behaved as expected: dolutegravir bound strongly to IN (−6.070) and PR (−7.319) with stable MD; nirmatrelvir was specific for M^pro and displayed weaker, discontinuous engagement at PL^pro/RdRp/RBD under identical settings. ADMET suggested conessine has excellent permeability/BBB access (high logP), but liabilities include poor aqueous solubility, predicted hERG risk, and CYP2D6 substrate dependence.Conessine operates as a hydrophobic, multi-target wedge with the most favorable computed engagement at HIV-1 PR/RT and the SARS-CoV-2 spike RBD, while maintaining stable poses at M^pro and RdRp. The scaffold merits medicinal-chemistry optimization to improve solubility and de-risk cardiotoxicity/CYP interactions, followed by biochemical and cell-based validation against prioritized targets. Full article

Oropouche virus (OROV) is an emerging arbovirus responsible for Oropouche fever, also known as sloth fever, a febrile illness that can lead to recurrent outbreaks in affected regions. Endemic to parts of South and Central America, OROV is primarily transmitted by biting midges (Culicoides paraensis), although mounting evidence implicates mosquitoes, particularly the Culex and Aedes species, as additional vectors. Recent ecological disturbances—such as deforestation, urbanization, and climate change—have driven significant shifts in vector population dynamics, contributing to the expanded geographic range and increased transmission of OROV. Notably, recent reports of OROV infections among American and European travelers to Cuba highlight the virus’s growing potential for international dissemination and underscore its significance as a global health concern. OROV is an enveloped orthobunyavirus within the Peribunyaviridae family, possessing a tripartite, single-stranded, negative-sense RNA genome composed of the S (small), M (medium), and L (large) segments. These segments encode the nucleocapsid (N) protein, glycoproteins (Gn and Gc), and RNA-dependent RNA polymerase, respectively. Despite increasing incidence and potential for global spread, no licensed vaccines or antiviral therapies currently exist, and effective diagnostic tools remain limited. Furthermore, although human-to-human transmission has not been observed, the absence of robust surveillance systems complicates timely outbreak detection and response. In this study, we present a comprehensive molecular characterization of OROV’s major structural proteins, with an emphasis on structural modeling and epitope prediction. By integrating bioinformatics approaches with available structural data, we identify key antigenic regions that could serve as targets for the development of serological diagnostics and vaccine candidates. Our findings contribute critical insights into the molecular virology of OROV and provide a foundational framework for future efforts aimed at the prevention, diagnosis, and control of this neglected tropical pathogen. These advancements are essential for mitigating the impact of OROV in endemic regions and reducing the risk of global emergence. Full article

Human rhinovirus (HRV) is the most common cause of upper respiratory tract infections and can cause substantial morbidity in children. Because its clinical features are nonspecific, differentiation from influenza virus and respiratory syncytial virus is often difficult, underscoring the diagnostic importance of real-time reverse transcriptase polymerase chain reaction (Real-Time RT-PCR)-based detection. This study aimed to characterize long-term epidemiological patterns of HRV in the Republic of Korea and assess their clinical and public health implications. We retrospectively analyzed 23,284 nasopharyngeal swab specimens collected between 2007 and 2024 from outpatients and inpatients presenting with influenza-like illness at a tertiary care hospital. HRV RNA was detected by Real-Time RT-PCR, and positivity rates were compared by year, month, and age group. Annual detection peaked in 2015 (31.3%) and 2016 (28.6%), then dropped sharply during the COVID-19 pandemic (2020–2021, 4.2–11.0%) and remained low through 2024. Seasonally, rates were highest in July (24.4%) and September (24.1%) and lowest in January (6.9%). Age-specific analysis showed peak positivity in children (26.1%) and infants (20.3%), with lower rates in adults (3.9%) and older adults (3.3%). These findings underscore the diagnostic value of HRV detection and provide evidence for pediatric-focused prevention, outbreak preparedness, and climate-informed surveillance strategies. Full article