Scutellarein Inhibits Osteosarcoma Growth by Targeting the TLR4/TRAF6/NF-κB Pathway

Drug Design Development and Therapy, Год журнала: 2025, Номер Volume 19, С. 51 - 64

Опубликована: Янв. 1, 2025

Osteosarcoma (OS) is the most common malignant tumor associated with poor patient outcomes and a limited availability of therapeutic agents. Scutellarein (SCU) monomeric flavone bioactive compound potent anti-cancer activity. However, effects mechanisms SCU on growth OS remain unknown. The Cell Counting Kit-8, colony formation assay 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays were used to analyze cell proliferation ability in vitro. TLR4/TRAF6/NF-κB signaling transduction was investigated by RNA sequencing analysis, quantitative real-time polymerase chain reaction, Western blotting, NF-κB luciferase reporter assay, immunofluorescent staining, immunoprecipitation. Molecular docking cellular thermal shift employed confirm binding interaction between TLR4. TLR4 overexpression analyzed using xenograft model immunohistochemical staining. found significantly inhibit proliferation, analysis suggested that pathway closely this process. Further studies revealed inhibited canonical through its TLR4, which disrupted TRAF6. Moreover, also repressed signal inhibiting expression. Furthermore, suppress targeting vitro vivo. exhibited dual impact expression disrupting TLR4-TRAF6 interaction, resulting inactivation, thereby blocking growth.

Язык: Английский

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Aquaporins modulate the cold response of Haemaphysalis longicornis via changes in gene and protein expression of fatty acids

Parasites & Vectors, Год журнала: 2025, Номер 18(1)

Опубликована: Фев. 24, 2025

Abstract Background As ectotherms that spend most of their life in the environment (off-host), ticks face challenges maintaining water balance, and some species must cope with severe low winter temperatures. Aquaporins (AQPs) are essential membrane proteins enhance cold tolerance many animals by regulating homeostatic processes. However, dynamic expressions involvement aquaporins stress remain unclear. Methods In present study, three AQP genes, HlAQP2 , HlAQP3 HlAQP5 belonging to major intrinsic protein (MIP) superfamily, were characterized from important vector tick Haemaphysalis longicornis . Then, multiple bioinformatics analyses performed. Quantitative real-time PCR (qPCR) was used detect different H. genes under treatment conditions. RNA interference explore relationship between response Additionally, proteomic transcriptomic investigate mechanisms underlying effects AQPs on ticks. Results The amino acid sequence shows high homology Ixodida, comprising two asparagine-proline-alanine (NPA) motifs, whereas featured glycerol facilitator GlpF channel. spatiotemporal expression varied significantly after temperature treatment, patterns observed over prolonged exposure periods. RNAi knockdown increased mortality at a sublethal − 14 °C for 2 h. Proteomic analysis revealed differentially expressed caused mainly enriched fatty metabolism pathway. Conclusions above results indicated could regulate modulating balance metabolism. Graphical

Язык: Английский

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Comprehensive SUMO Proteomic Analyses Identify HIV Latency-Associated Proteins in Microglia

Cells, Год журнала: 2025, Номер 14(3), С. 235 - 235

Опубликована: Фев. 6, 2025

SUMOylation, the post-translational modification of proteins by small ubiquitin-like modifiers, plays a critical role in regulating various cellular processes, including innate immunity. This is essential for modulating immune responses and influencing signaling pathways that govern activation function cells. Recent studies suggest SUMOylation also contributes to pathophysiology central nervous system (CNS) viral infections, where it host response replication dynamics. Here, we explore multifaceted its implications infections within CNS. Notably, present novel proteomic analyses aimed at elucidating ubiquitin-related modifier (SUMO) human immunodeficiency virus (HIV) latency microglial Our findings indicate may regulate key involved maintaining latency, suggesting potential mechanism which HIV evades detection By integrating insights from proteomics with functional studies, anticipate these be groundwork future on HIV–host interactions mechanisms underlie during latent productive infection.

Язык: Английский

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Intracellular HIV-1 Tat regulator induces epigenetic changes in the DNA methylation landscape

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Март 4, 2025

Introduction The HIV regulatory protein Tat enhances viral transcription and also modifies host gene expression, affecting cell functions like cycle apoptosis. Residual expression of is detected in blood other tissues even under antiretroviral treatment. Cohort studies have indicated that, despite virologic suppression, people with (PWH) are at increased risk comorbidities linked to chronic inflammation, accelerated immune ageing, cellular senescence, sometimes associated abnormal genomic methylation patterns. We analysed whether influences DNA subsequently impacts the transcriptional signature, contributing inflammation ageing. Methods transfected Jurkat cells full-length (Tat101), Tat’s first exon (Tat72), or an empty vector (TetOFF). assessed modifications via Infinium MethylationEPIC array, we evaluated transcriptomic alterations through RNA-Seq. Methylation levels promoters body regions were correlated their data, subsequently, performed overrepresentation analysis identify biological terms containing differentially methylated expressed genes. Results Tat101 caused significant hyper- hypomethylation changes individual CpG sites, resulting slightly global hypermethylation. bodies resulted altered specifically regulating 5.1% genes (DEGs) Tat101- expressing cells. In contrast, Tat72 had a minimal impact on this epigenetic process. observed involved inflammatory responses, lipid antigen presentation, Discussion infection may constitute key modelling actor that contributes pathogenesis inflammation. Clinical interventions targeting blockade reduce senescence related comorbidities.

Язык: Английский

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HIV-1 Vpu and SARS-CoV-2 ORF3a proteins disrupt STING-mediated activation of antiviral NF-κB signaling

Science Signaling, Год журнала: 2025, Номер 18(870)

Опубликована: Янв. 21, 2025

Activation of the stimulator interferon genes (STING) pathway by cytosolic DNA leads to activation transcription factors regulatory factor 3 (IRF3) and nuclear κB (NF-κB). Although many viruses produce proteins that inhibit IRF3-dependent antiviral responses, some STING-induced NF-κB without blocking IRF3 activation. Here, we found STING-activated, NF-κB–dependent, IRF3-independent innate immunity inhibited replication virus herpes simplex type 1 (HSV-1), RNA coxsackievirus A16 (CV-A16), retrovirus HIV-1. The HIV-1 nonstructural protein Vpu bound STING prevented it from interacting with upstream kinase inhibitor subunit β (IKKβ), thus signaling. This function was conserved among diverse simian immunodeficiency strains distinct its action in disrupting other host pathways. Furthermore, ORF3a coronavirus SARS-CoV-2 also promoted viral activity but not IRF3. These findings demonstrate have convergently evolved selectively NF-κB–mediated downstream activation, suggesting targeting this may represent a promising strategy.

Язык: Английский

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Zebrafish TDP43 positively regulates p65-mediated apoptotic pathway

International Journal of Biological Macromolecules, Год журнала: 2025, Номер unknown, С. 142599 - 142599

Опубликована: Март 1, 2025

Язык: Английский

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SLC38A9 is directly involved in Tat-induced endolysosome dysfunction and senescence in astrocytes

Life Science Alliance, Год журнала: 2025, Номер 8(7), С. e202503231 - e202503231

Опубликована: Май 5, 2025

Cellular senescence contributes to accelerated aging and the development of various neurodegeneration disorders including HIV-associated neurocognitive disorders. The is attributed, at least in part, CNS persistence HIV-1 transactivator transcription (Tat), an essential protein for viral that actively secreted from HIV-1–infected cells. Secreted Tat enters cells via receptor-mediated endocytosis induces endolysosome dysfunction cellular Given represents early step exogenous Tat-induced senescence, we tested hypothesis endolysosome-dependent mechanism human astrocytes. We demonstrated internalized interacts with endolysosome-resident arginine sensor SLC38A9 arginine-rich basic domain. Such interaction between leads dysfunction, enhanced LTR transactivation, senescence. These findings suggest drives highlight novel role astrocyte

Язык: Английский

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PRMT3 reverses HIV-1 latency by increasing chromatin accessibility to form a TEAD4-P-TEFb-containing transcriptional hub

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Май 15, 2025

Latent HIV-1 presents a formidable challenge for viral eradication. transcription and latency reversal require interactions between the promoter host proteins. Here, we perform dCas9-targeted locus-specific protein analysis discover interaction of human arginine methyltransferase 3 (PRMT3) with promoter. This reverses in cell line models primary cells from latently infected persons by increasing levels H4R3Me2a factor P-TEFb at PRMT3 is found to promote chromatin accessibility small subset genes regions harboring classical recognition motif another TEAD4. attracts TEAD4 synergistically activate transcription. Physical among PRMT3, P-TEFb, exist, which may help form transcriptional hub Our study reveals potential targeting these proteins eradicate latent HIV-1.

Язык: Английский

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Targeting HIV-1 Immune Escape Mechanisms: Key Advances and Challenges in HIV-1 Vaccine Design

Microbiological Research, Год журнала: 2025, Номер 299, С. 128229 - 128229

Опубликована: Май 21, 2025

Despite numerous efforts, a successful vaccine against HIV-1 remains elusive. An effective must overcome the virus's sophisticated immune evasion strategies and induce production of broadly neutralizing antibodies to counteract HIV-1's rapid mutation, replication, transmission within between hosts. predominantly evades recognition clearance through mechanisms such as genomic mutations, alterations in envelope protein affinity, formation latent viral reservoirs, interference with major histocompatibility complex class I antigen presentation. Although considerable efforts have focused on generating potent vaccines that elicit bnAbs, probability achieving exceedingly low given immune-evasive tactics. This review discusses principal highlights latest progress research, providing fresh perspectives insights for design vaccines.

Язык: Английский

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Tumor Necrosis Factor Receptor-Associated Factors (TRAFs): Key Regulatory Factors in Antiviral Defence

Microbial Pathogenesis, Год журнала: 2025, Номер 206, С. 107755 - 107755

Опубликована: Май 26, 2025

Язык: Английский

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