Search Results (134)

Inflammation is essential for host defense, but, when dysregulated, it contributes to tissue damage and chronic disease. MicroRNA-146a (miR-146a) is a well-recognized negative regulator of inflammatory signaling, primarily through suppression of the NF-κB pathway; however, its broader proteomic impact under inflammatory conditions remains incompletely defined. In this study, we overexpressed an miR-146a mimic in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and applied quantitative mass spectrometry to characterize global protein abundance changes. Functional overexpression was supported by reduced mRNA abundance of the established miR-146a targets TRAF6 and IRAK1 under LPS-stimulated conditions. Proteomic analysis identified 1232 proteins showing differential abundance under the predefined exploratory criteria, including proteins related to NF-κB activity, inflammasome components, nitric oxide synthesis, and IL-6-associated pathways. Proteins linked to interferon-related signaling were also altered. Targeted validation by quantitative RT-PCR and parallel reaction monitoring supported changes in selected inflammatory mediators, including PTGS2, NOS2, MAPKAPK2, and IRF3. Functionally, miR-146a overexpression was associated with reduced LPS-induced nitric oxide and IL-6 production. Together, these findings provide an exploratory proteomic overview of pathways associated with miR-146a overexpression in activated macrophages and suggest that miR-146a is associated with modulation of multiple inflammatory signaling networks under inflammatory conditions. Full article

Diabetic retinopathy (DR) reflects retinal microvascular injury and systemic immune-metabolic stress, and most public DR transcriptomic datasets lack paired microbiome/metabolomic profiles. We used gutMGene v2.0 as a curated microbe/metabolite–host gene prior and integrated it with peripheral blood transcriptomics from GSE221521. Candidate genes were refined by weighted gene co-expression network analysis (WGCNA), repeated resampling, cross-dataset assessment, mechanism scoring, peripheral blood mononuclear cell (PBMC) single-cell localization and filamin A (FLNA)-centered single-cell gene regulatory network (GRN) virtual knockout. The gutMGene prior contained 238 host genes; 15 DR-associated genes overlapped this prior, and WGCNA retained ten candidate gut microbe and microbial metabolite-related genes (GMMRGs): FLNA, AKT1, IRAK1, BCL10, CDK6, CTSD, JUP, CXCL1, CXCR2 and IL4R. Resampling prioritized FLNA as the most consistent candidate. Cross-dataset assessment localized the strongest signal to type 2 diabetes (T2D) PBMCs, retinal endothelial cells and advanced proliferative diabetic retinopathy with diabetic macular edema (PDR + DME) retinal tissue, with weaker separation in whole blood, broad retinal tissue and six-donor type 1 diabetes (T1D) PBMCs. FLNA virtual knockout predicted cell-context-dependent perturbation of immune-related transcriptional programs, including IL4R in DR B cells and CTSD in DR monocytes/NK cells. This prior-guided study identifies FLNA within a ten-gene GMMRG set as a circulating host-response signal that links curated microbe/metabolite–host records to immune-vascular and cytoskeletal remodeling in DR. Full article

Background and Objectives: The clinical differentiation of peripheral involvement within the spondyloarthritis (SpA) spectrum remains a significant challenge. Identifying patients at the stage of psoriasis without clinical arthritis (PsO), before the onset of overt arthritis, is crucial for early disease management. MicroRNAs (miRNAs) have emerged as potential epigenetic regulators in inflammatory rheumatic diseases. This study aimed to identify circulating miRNA profiles that serve as discriminative biomarkers between PsO and peripheral SpA (p-SpA). Materials and Methods: This exploratory study was conducted in two phases. In the preliminary discovery phase, plasma miRNA expression was analyzed using high-throughput microarrays in patients with p-SpA (modeled by peripheral psoriatic arthritis, n = 6), PsO (psoriasis without clinical arthritis, n = 3), and osteoarthritis (n = 3). In the validation phase, candidate miRNAs were verified using TaqMan-based qPCR in an independent cohort (n = 30) of various SpA phenotypes, categorized into those with peripheral arthritis (SpA-A) and those without (SpA-N). Results: The preliminary discovery phase identified altered levels of hsa-miR-140-5p, hsa-miR-192-5p, and hsa-miR-146a-5p among the groups; however, due to the small sample size, these initial findings required strict downstream verification. Functional enrichment analysis revealed that these candidate miRNAs primarily targeted the NF-κB signaling pathway (hsa04064) and Toll-like receptor (TLR) signaling pathway (hsa04620). The validation cohort confirmed that these three miRNAs could reliably differentiate SpA-A from SpA-N patients. Furthermore, bioinformatic mapping predicted that downstream targets, including TRAF6, IRAK1, and CXCL2, may be associated with these clinical phenotypes, serving as hypothesis-generating observations for future studies. Conclusions: Our findings suggest that specific plasma miRNA profiles are associated with the inflammatory pathways driving peripheral involvement in the SpA spectrum. These miRNAs represent potential biomarkers associated with peripheral arthritis in the SpA spectrum. While they offer new molecular insights into disease pathogenesis, their predictive value for identifying PsO patients at risk of developing overt arthritis requires confirmation in future longitudinal studies. Full article

Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, leading to multi-organ dysfunction. Toll-like receptor signaling via MYD88- and TRIF-dependent pathways plays a central role in this process; however, its temporal and tissue-specific dynamics remain incompletely understood. The aim of this study was to investigate time-dependent transcriptional changes in MYD88- and TRIF-dependent signaling pathways across multiple organs in a murine model of sepsis. mRNA expression of MYD88, IRAK1, IRAK4, NF-kB, CCL4, CCL20, CCR2, IFN-β, IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-18, Klotho, KLF4, HOXA5, NANOG and HIF1α was quantified using qRT-PCR in intestinal, kidney, liver and lung tissues at 24, 48, and 72 h following cecal ligation and puncture-induced sepsis in male C57BL/6J mice. Significant upregulation of innate immune signaling molecules, cytokines, chemokines, and interferon-related genes was observed in all tissues compared with controls. Genes associated with hypoxia and cellular regulation were also increased. These responses were tissue-specific and progressively intensified over time. Sepsis represents a dynamic, time-dependent, and tissue-specific process characterized by sustained activation of immune and hypoxic pathways, providing potential targets for time-stratified therapeutic strategies. Full article

Myelodysplastic syndromes are clonal hematopoietic neoplasms in which ineffective hematopoiesis arises within the context of chronic inflammation and immune dysregulation. Growing evidence indicates that aging-associated inflammaging and inflammation-driven remodeling of the bone marrow microenvironment are not secondary phenomena, but active forces that shape clonal selection, lineage commitment, and disease evolution. This narrative review integrates recent insights from translational immunology, stem cell biology, multi-omics analyses, and clinical studies to examine the reciprocal interplay between inflammation and myelodysplastic syndrome pathogenesis. Chronic inflammatory stress imposes selective pressure on hematopoietic stem cells, favoring the expansion of mutation-bearing clones characteristic of clonal hematopoiesis and overt disease. As inflammation persists, immune dysfunction, together with stromal alterations, progressively reinforce ineffective hematopoiesis and clonal dominance. Genetic lesions, including TP53 and spliceosome mutations, further amplify inflammatory signaling and reshape the marrow niche, conferring clonal fitness and genomic instability. Clinically, readily accessible peripheral blood inflammatory indices reflect these biological processes and correlate with prognosis and therapeutic response. Collectively, these observations position inflammation as a unifying determinant of myelodysplastic syndrome initiation, progression, and treatment sensitivity. Integrating inflammatory signatures with genomic profiling may refine risk stratification and support the development of therapeutic strategies aimed at restoring marrow homeostasis and limiting inflammation-driven clonal evolution. Full article

Background/Objectives: Our prior work demonstrated that a non-synonymous mutation in procollagen type III (Col3a1) at residue 33 (C33S) was responsible for the skin fibrosis seen in the Tsk2/+ mouse. We previously showed increased expression of the TWEAK receptor/fibroblast growth factor–inducible 14 (FN14) in Tsk2/+ skin and systemic sclerosis (SSc) skin; however, the role of TWEAK in Tsk2/+ had not been assessed. Methods: Primary dermal fibroblasts from Tsk2/+ and WT mice were examined for differential gene expression at different ages. Wild-type and C33S-mutated COL3A1-expressing plasmids were transfected into Col3a1KO fibroblasts and treated with FN14 or TGF-β inhibitors. Results: Tsk2/+ mice had increased FN14 protein compared to their respective non-diseased counterparts and had increased mRNA expression of a panel of transcripts associated with a fibrotic signature (Icam1, Irak2, and Tweak). COL3A1-KO cells transfected with a COL3A1^Tsk2-expressing plasmid displayed significantly higher levels of this fibrotic signature compared to COL3A1^WT-expressing plasmid. FN14 and TGFBR1 inhibitors significantly reduced the fibrotic signature compared to untreated Tsk2/+ cells. Conclusions: The upregulation of FN14 in Tsk2/+ mouse skin and primary dermal fibroblasts suggests that this pathway may be crucial to fibrosis development. Inhibition of both FN14 and TGFBRI reduces the fibrotic signature in both Col3a1Tsk2 transfections, suggesting a similarity between the Tsk2/+ model and SSc and confirming that the Tsk2/+ mouse model is suitable for studying the initiating events of SSc fibrosis. Full article

Background/Objectives: As important post-transcriptional and epigenetic regulators of gene expression, miRNAs play a pivotal role in modulating host–virus interactions. While prior reviews have addressed either direct miRNA–HIV genome interactions or miRNA-mediated immune modulation in isolation, the integrated dual functionality of these molecules has not been systematically characterized. This review aimed to comprehensively explore how miRNAs that target the HIV-1 genome simultaneously modulate key innate and adaptive host immune signaling pathways. The conceptual novelty of this study is determined not by the identification of previously unknown miRNA-target gene pairs, but by the systemic integration of two regulatory levels (direct inhibition of the viral genome and modulation of the host cell immune signaling pathways) within a unified analytical framework. Such an integrated approach reveals a proviral regulatory network that remains non-obvious when each of these levels is examined separately. Methods: A narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar (all years through 2025). In Stage 1, publications reporting experimentally confirmed interactions between host miRNAs and the HIV-1 genome were identified, yielding a curated set of 15 miRNAs. In Stage 2, target genes for each miRNA were retrieved from miRTarBase, TarBase (experimentally validated) and TargetScan 8.0 (in silico predicted). In Stage 3, target genes were manually mapped to key immune signaling pathways (TLR, NF-κB, JAK-STAT). In Stage 4, targeted literature searches were performed for each miRNA–target gene pair to identify direct experimental evidence of interaction. All stages were performed by two independent researchers, with discrepancies resolved by a third. Results: Fifteen host miRNAs with experimentally confirmed binding to the HIV-1 genome were identified, targeting viral genes including nef, pol, vpr, gag, env, vif, and the 3′-UTR. Thirteen of these miRNAs were found to regulate components of major immune pathways. miR-92a-3p, miR-29a/b-3p, miR-150-5p, and miR-125b-5p emerged as the most pleiotropic regulators, simultaneously suppressing TLR signaling (TLR3, TLR7, TLR8, MyD88, TRAF3/6, IRAK1/4), NF-κB components (REL, RELA, NFKB1), JAK-STAT effectors (STAT1–3, STAT5A/B, JAK2), and negative regulators of cytokine signaling (SOCS and PIAS family proteins). miR-133b and miR-196b-5p were found to selectively regulate SOCS/PIAS proteins without involvement in other analyzed pathways, suggesting potential for selective therapeutic targeting. Conclusions: The analyzed miRNAs exhibit functional dualism, acting as direct post-transcriptional suppressors of the HIV-1 genome while simultaneously functioning as epigenetic modulators of host immune signaling. These two modes of action are not independent but together form a conceptual framework of a self-reinforcing proviral regulatory network that, based on the synthesis of published evidence, is proposed to promote viral latency and immune evasion. The identified miRNAs represent promising, albeit complex, targets for novel therapeutic strategies aimed at eliminating latent HIV reservoirs. Full article

Background/Objectives: Chronic myeloid leukemia (CML), essential thrombocythemia (ET), primary myelofibrosis (PMF), and polycythemia vera (PV) are myeloproliferative neoplasms (MPNs) that require precise molecular characterization. Although driver mutations such as BCR-ABL1 and JAK2 are diagnostically important, they do not fully explain disease heterogeneity. The NanoString nCounter^® system enables direct multiplex gene expression analysis without RNA amplification and is suitable for degraded bone marrow specimens. This study aimed to analyze cytokine gene expression in bone marrow mononuclear cells of patients with MPNs and controls using NanoString technology, identify differentially expressed genes (DEGs) among MPN subtypes, and investigate their biological significance. Methods: Bone marrow aspirates were collected from 19 patients with MPNs (CML, ET, PMF, and PV) and 6 control patients. Mononuclear cells were isolated, and RNA expression of a 40-gene cytokine panel was analyzed using the NanoString nCounter^® system with strict quality control and normalization. DEGs were identified for each MPN subtype, followed by Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analyses. Results: CML and PV demonstrated 20 and 12 DEGs, respectively. In contrast, ET showed only one DEG (IRAK2), and PMF showed none. Functional analyses revealed enrichment of cytokine signaling, Toll-like receptor (TLR), and JAK-STAT pathways in CML, indicating immune and inflammatory dysregulation. PV DEGs were associated with TLR signaling, IL-17 pathways, and cytokine–cytokine receptor interactions, suggesting active cytokine-mediated inflammation. Conclusions: CML and PV exhibited distinct cytokine-driven transcriptional signatures, whereas ET and PMF exhibited minimal alterations. These findings support the clinical utility of NanoString technology for bone marrow specimens and highlight disease-specific immune pathways as potential diagnostic biomarkers in MPNs. Full article

Gingivitis, periodontitis, and stomatitis are common oral inflammatory disease affecting a large proportion of the global population. Increasing attention has recently been given to the development of health functional materials aimed at maintaining oral health and preventing microbial-associated oral disease. This study evaluated the efficacy of the lipoteichoic acid (LTA) fraction derived from the probiotic Lactiplantibacillus plantarum K8 (pLF) in preventing oral inflammation and microbial infection using the oral epithelial cell line YD-38. The results confirmed that pLF enhances the expression of interleukin-1 receptor-associated kinase M (IRAK-M), a negative regulator of Toll-like receptor (TLR) signaling, and inhibits the expression of pro-inflammatory cytokines, including C-C motif ligand 2 (CCL2), interleukin-6 (IL-6), and interleukin-8 (IL-8), in YD-38 cells stimulated with tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Furthermore, it was demonstrated that pLF induces IRAK-M expression in a TLR2-involved manner and inhibits nuclear factor-kappa B (NF-κB) signaling, thereby reducing the expression of pro-inflammatory cytokines. pLF also exhibits oral antimicrobial efficacy by increasing the expression of the antimicrobial peptide human β-defensin 1 (hBD1) and human β-defensin 2 (hBD2) in a TLR2-involved manner and effectively inhibiting the growth of Porphyromonas gingivalis and Staphylococcus aureus in the epithelial cell associated system. Therefore, the LTA fraction derived from L. plantarum K8 represents a promising postbiotic candidate for the regulation of oral immune and microbial responses. Full article

Background: A20, encoded by tumor necrosis factor alpha-induced protein 3 (TNFAIP3), is a key negative regulator of NF-κB signaling with context-dependent functions in cancer. Its role in renal cell carcinoma (RCC), particularly clear-cell RCC (ccRCC), remains incompletely defined. Methods: Public GEO transcriptomic data from 23 controls and 32 ccRCC samples were analyzed using gene set enrichment analysis (GSEA). A20-overexpressing HEK293 and 786-O cells were assessed by functional assays and transcriptomic profiling. Eight ccRCC FFPE samples were profiled to compare A20-associated transcriptional patterns with cell-line data. Targeted DNA sequencing was performed in 11 ccRCC and 8 papillary RCC samples, and whole-exome sequencing was conducted in A20-overexpressing 786-O cells. Key genes were further evaluated using Kaplan-Meier survival analysis in 530 ccRCC patients and TCGA-KIRC data comprising 533 primary tumors and 72 normal samples. Results: GEO analysis showed significant TNFAIP3/A20 upregulation in ccRCC (p = 3.96 × 10⁻⁵) and enrichment of NF-κB-related gene sets (p = 0.01). A20 overexpression produced distinct phenotypes in HEK293 and 786-O cells. In HEK293 cells, A20 increased BIK and ARHGAP6 expression and was associated with increased apoptosis and reduced wound closure. In 786-O cells, A20 suppressed ARHGAP6 and APAF1 and was associated with increased proliferation, enhanced wound closure, and reduced apoptosis relative to EV controls. A20-high ccRCC samples showed enrichment of NF-κB, TGF-β, DNA repair, mTOR/metabolic, hypoxia, and proteasome-related pathways. Genomic analyses identified alterations in NF-κB-related genes, including CARD10 and IRAK1. Conclusions: A20/TNFAIP3 may exert cell-context-dependent effects in RCC and is associated with tumor-relevant transcriptional and genomic alterations requiring further validation. Full article

VEXAS (Vacuoles, E1 ubiquitin-activating enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a systemic disorder characterized by an overlap of hematologic and inflammatory features. Most patients require chronic use of moderate-to-high doses of glucocorticoids (GCs) to maintain disease control. Data on GC-sparing therapies is limited, and there have been no prospective pharmacotherapeutic trials in VEXAS syndrome published to date. Pacritinib, an oral inhibitor of IRAK1, JAK2, and ACVR1, has emerged as a promising therapeutic option for VEXAS syndrome. The PAXIS trial is the first prospective, randomized pharmacotherapeutic study conducted in this rare and severe disease. Utilizing a novel study design and disease-specific endpoints, the trial will evaluate the efficacy and safety of two dose levels of pacritinib compared with placebo in patients with VEXAS syndrome (NCT06782373, EUCTR: 2024-516347-41-00). Full article

Objectives: This study evaluated the effects of modified Gamchogeongang-tang (GGS01) on lung injury using a COPD mouse model. Methods: C57BL/6 mice were exposed to cigarette smoke extract and lipopolysaccharide and treated with GGS01 (100, 200, or 400 mg/kg). Bronchoalveolar lavage fluid (BALF) and lung tissue were analyzed using cytospin, enzyme-linked immunosorbent assay, real-time polymerase chain reaction (PCR), flow cytometry analysis, hematoxylin and eosin (H&E) and Masson’s trichrome staining, and immune histology fluorescent staining. Results: GGS01 significantly inhibited the increase in neutrophils in BALF, decreased immune cell activity in BALF and lung tissue, and inhibited the increase in the levels of IL-1α, TNF-α, IL-17A, MIP2, and CXCL-1 in BALF. Conclusions: Real-time PCR analysis showed that MUC5AC mRNA expression in lung tissue significantly decreased compared with the control group. The score of histological analysis of lung tissue damage was significantly reduced, and a decrease in IRAK1 and TNF-α expression in lung tissue was observed. Full article

Despite antiretroviral therapy, HIV proteins, such as Tat, persist in tissues, driving chronic inflammation. Cervical inflammation in females not only accelerates HIV progression but also increases the risk of other STIs; hence, understanding the underlying factors/regulators is vital. However, Tat-induced cervical inflammation and its regulation are hitherto poorly understood, which we investigated using TZM-bl cells. Tat stimulation in these cervical epithelial cells significantly increased the expression of various inflammatory mediators, including cytokines (IL-1β, TNF-α, IL-6, IL-17a, GM-CSF), chemokines (MIP-1α, MIP-1β), adhesion molecules (ICAM-1, P-Selectin, E-Selectin), and ROS. Further upregulation of inflammatory mediators (NF-κB, IRAK-4) along with TLR7 was observed in Tat-stimulated cells. Interestingly, Tat stimulation decreased miR-204-5p expression in these cells, suggesting a role in regulating Tat-mediated inflammatory processes. Using a gain-of-function approach, we further observed that the overexpression of miR-204-5p reduced the expression of IL-1β, TNF-α, IL-6, MIP-1α, MIP-1β, ICAM-1, P-Selectin, and ROS in the Tat-stimulated TZM-bl cells, along with NF-κB, IRAK-1, and IRAK-4. Using Western blotting and luciferase assays, miR-204-5p was further shown to directly target NF-κB. Here, we report that HIV-1 Tat stimulation in cervical epithelial cells downregulates hsa-miR-204-5p, thereby activating the pro-inflammatory TLR7/NF-κB axis, highlighting its relevance to understanding mechanisms underlying cervical inflammation. Full article

To investigate the regulatory effects of miR-16-5p and miR-142-3p on inflammation and autophagy in human corneal epithelial cells (HCEpiCs) exposed to hyperosmotic stress, a key pathogenic condition in dry eye disease, HCEpiCs were cultured under NaCl-induced hyperosmotic conditions (450 mOsm, 24 h) and transfected with miR-16-5p or miR-142-3p mimics. Expression of inflammatory cytokines (IL-1β, IL-6, TNF-α, IRAK1), autophagy-related genes (ATG5, Beclin-1, ATG16L1, p62), and apoptotic markers (Bax, Bcl-2, caspase-3) was analyzed by qRT-PCR and Western blot. Reactive oxygen species (ROS), autophagic vesicles, and apoptosis were evaluated using DCFH-DA, DAPRed, and Annexin V assays. The expression levels of antioxidant proteins (SOD1, catalase, NRF2) were also measured. Hyperosmotic stress induces marked inflammatory activation and excessive autophagy in HCEpiCs, accompanied by increased ROS generation and apoptosis. Overexpression of miR-16-5p or miR-142-3p significantly attenuated these effects by suppressing NF-κB-mediated cytokine expression and downregulating ATG5 and ATG16L1 expression, while restoring p62 expression. Both miRNAs reduced oxidative stress and COX-2 expression, enhanced antioxidant defenses, and normalized the expression of apoptotic markers. miR-16-5p and miR-142-3p are important regulators of inflammation and autophagy under hyperosmotic stress. Our findings suggest that modulating intracellular miR-16-5p and miR-142-3p levels in corneal epithelial cells may represent a potential approach to protect the ocular surface under hyperosmotic stress, although their systemic roles in autoimmune dry eye require further clarification. Full article

The substantial interest in plant-based drugs or plant-derived phytocompounds drives researchers to conduct comprehensive investigations on their therapeutic properties. Mollugin, one of the major active constituents of Rubia cardifolia, has been well-studied for its pharmacological properties, demonstrating potent anti-inflammatory properties by suppressing the TAK-1-mediated activation of NF-κB/MAPK and enhancing the Nrf2/HO-1-mediated antioxidant response. It exhibits strong anticancer effects through ferroptosis via IGF2BP3/GPX4 pathways, induces mitochondrial apoptosis, and targets NF-κB, ERK, and PI3K/Akt/mTOR to suppress tumor progression. Mollugin also inhibits JAK2/STAT and PARP1 pathways, suppressing IL-1β expression via the modulation of ZFP91. Moreover, it regulates the MAPK/p38 pathway, promotes neuroprotection, and improves cognitive performance through GLP-1 receptor activation. Mollugin promotes osteogenesis by activating the BMP-2/Smad1/5/8 signaling pathway and downregulates MAPK, Akt, and GSK3β expression, leading to the inhibition of osteoclastogenesis. It overcomes multidrug resistance by downregulating MDR1/P-gp, CREB, NF-κB, and COX-2 through AMPK activation. Its antibacterial effect is mediated by strong binding to FUR, UDP, and IpxB proteins in Enterobacter xiangfangensis. Mollugin mitigates Klebsiella pneumoniae infection, suppresses adipogenesis without causing cytotoxicity, and protects endothelial cells via the BDNF/TrkB-Akt signaling pathway. Synthetic derivatives of mollugin, such as oxomollugin and azamollugin, have shown enhanced anticancer and anti-inflammatory effects by regulating EGFR, PKM2, TLR4/MyD88/IRAK/TRAF6, and NF-κB/IRF3 pathways with improved solubility and stability. Collectively, these findings emphasize the broad-spectrum activity of mollugin. This review provides a critical interpretation of the mechanistic pathways regulated by mollugin and its derivatives, emphasizing their pharmacological significance and exploring their potential for future translation as multitarget drug candidates. Full article