BACKGROUND: Synovial inflammatory hyperplasia is the key pathological process that leads to further joint damage in rheumatoid arthritis (RA) progress. Kadsura heteroclita (Roxb) Craib, also called Xuetong in Chinese Tujia ethnomedicine, is utilized for its medicinal properties, including promoting blood circulation, dispelling \"wind evil\", and relieving \"damp evil\". It has been used in the treatment of arthralgia and RA, within Tujia ethnomedicinal practices. Xuetongsu (XTS), the main component of Xuetong, has been shown to inhibit the proliferation of RA fibroblast-like synovial cells (RAFLS) cells. However, the molecular mechanism of XTS in RA treatment requires further investigation.
OBJECTIVE: To observe the therapeutic effect of XTS on synovial inflammatory hyperplasia in rheumatoid arthritis, focusing on its underlying molecular mechanisms involving the janus kinase 2 (JAK2)/transducer/activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) signaling pathways.
METHODS: Protein-protein interaction (PPI) and molecular docking were used to find the main targets of XTS treatment for RA. In lipopolysaccharide (LPS)-induced RAFLS and RAW264.7 cells in vitro models, the levels of inflammatory cytokines were analyzed using enzyme linked immunosorbent assay (ELISA), and the expression of JAK2, STAT3, and NF-κB signaling pathways, as well as cyclooxygenase-2 (COX-2), were analyzed through western blotting test. A hemolysis assay was used to certify the biosecurity of XTS. A model of adjuvant arthritis (AIA) was established in 40 male rats, and different doses of XTS were administered, followed by an automatic blood routine, ELISA assay, hematoxylin and eosin (H&E) staining, and radiological analysis of the effect of no XTS on blood cytokines, histological changes, and improvement of posterior paw bone destruction in AIA rats. The protein levels of inflammatory cytokines were analyzed by immunofluorescence, immunohistochemistry, or western blot. Finally, H&E staining was used to detect the damage of XTS on the heart, liver, spleen, lung, and kidney of AIA rats.
RESULTS: Our results demonstrate that XTS effectively inhibited LPS-induced inflammatory responses in RAFLS and RAW264.7 cells by modulating the JAK2/STAT3 and NF-κB signaling pathways. Moreover, XTS administration in the AIA rats model significantly ameliorated paw swelling. Histological analysis revealed that XTS also suppressed the inflammatory response in paw tissue by modulating the JAK2/STAT3 and NF-κB signaling pathways. Importantly, during the treatment, XTS exhibited excellent safety profiles, as it did not induce any abnormalities in blood routine parameters or cause organ damage in the rats.
CONCLUSIONS: Our findings highlight XTS as a promising natural agent for inhibiting synovial hyperplasia in RA. XTS holds great potential as an unprecedented natural agent for developing novel therapeutic strategies to target synovial hyperplasia in RA.

The gastrointestinal tract is chronically inflamed in ulcerative colitis (UC), which has a complicated etiology involving immunological, environmental, and genetic factors. The inflammatory response that is typical of UC is significantly regulated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Latest research has displayed that NF-κB signaling is controlled by three main types of non-coding RNAs (ncRNAs): circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs). These ncRNAs can change the expression of key genes within the NF-κB pathway by acting as molecular sponges, transcriptional regulators, and epigenetic modifiers. This review synthesizes current knowledge on the functions by which ncRNAs modulate NF-κB signaling in UC, discusses their potential as biomarkers for disease prognosis and diagnosis, and explores their therapeutic potential. Understanding the intricate interactions between ncRNAs and NF-κB signaling may provide novel insights into UC pathogenesis and targeted therapeutic strategies.

[This corrects the article DOI: 10.3389/fphar.2024.1361561.].

BACKGROUND: Osteoarthritis (OA) is a common musculoskeletal disorder characterized by chondrocyte apoptosis and extracellular matrix degradation. This study aimed to investigate the role of CCL4/CCR5 in regulating chondrocyte apoptosis and reactive oxygen species (ROS) levels in OA progression.
METHODS: Bioinformatics analysis was employed to identify CCL4 as the target gene, following which primary chondrocytes were treated with varying concentrations of CCL4. Apoptosis rate of chondrocytes and ROS levels were assessed using flow cytometry. The mechanism by which CCL4 regulated the extracellular matrix was investigated through Western blot and Immunofluorescence analyses. Additionally, maraviroc, a CCR5 inhibitor, was administered to chondrocytes in order to explore the potential signaling pathway of CCL4/CCR5.
RESULTS: Our study found that CCL4 was predominantly up-regulated among the top 10 hub genes identified in RNA-sequencing analysis. Validation through quantitative polymerase chain reaction (qPCR) confirmed elevated CCL4 expression in patients with Hip joint osteoarthritis, knee joint osteoarthritis, and facet joint osteoarthritis. The upregulation of CCL4 was associated with an increase in chondrocyte apoptosis and ROS levels. Mechanistically, CCL4, upon binding to its receptor CCR5, triggered the downstream phosphorylation of P65 in the nuclear factor-κB (NF-κB) signaling pathway. In vitro experiments demonstrated that treatment with maraviroc mitigated chondrocyte apoptosis, reduced intracellular ROS levels, and attenuated extracellular matrix degradation.
CONCLUSIONS: The study highlights the critical role of CCL4/CCR5 in modulating chondrocyte apoptosis and ROS levels in OA progression. Targeting this pathway may offer promising therapeutic interventions for mitigating the pathogenic mechanisms associated with OA.

UNASSIGNED: Spinal cord injuries (SCIs) trigger a cascade of detrimental processes, encompassing neuroinflammation and oxidative stress (OS), ultimately leading to neuronal damage. Phillygenin (PHI), isolated from forsythia, is used in a number of biomedical applications, and is known to exhibit anti-neuroinflammation activity. In this study, we investigated the role and mechanistic ability of PHI in the activation of microglia-mediated neuroinflammation and subsequent neuronal apoptosis following SCI.
UNASSIGNED: A rat model of SCI was used to investigate the impact of PHI on inflammation, axonal regeneration, neuronal apoptosis, and the restoration of motor function. In vitro, neuroinflammation models were induced by stimulating microglia with lipopolysaccharide (LPS); then, we investigated the influence of PHI on pro-inflammatory mediator release in LPS-treated microglia along with the underlying mechanisms. Finally, we established a co-culture system, featuring microglia and VSC 4.1 cells, to investigate the role of PHI in the activation of microglia-mediated neuronal apoptosis.
UNASSIGNED: In vivo, PHI significantly inhibited the inflammatory response and neuronal apoptosis while enhancing axonal regeneration and improving motor function recovery. In vitro, PHI inhibited the release of inflammation-related factors from polarized BV2 cells in a dose-dependent manner. The online Swiss Target Prediction database predicted that toll-like receptor 4 (TLR4) was the target protein for PHI. In addition, Molecular Operating Environment software was used to perform molecular docking for PHI with the TLR4 protein; this resulted in a binding energy interaction of -6.7 kcal/mol. PHI inhibited microglia-mediated neuroinflammation, the production of reactive oxygen species (ROS), and activity of the NF-κb signaling pathway. PHI also increased mitochondrial membrane potential (MMP) in VSC 4.1 neuronal cells. In BV2 cells, PHI attenuated the overexpression of TLR4-induced microglial polarization and significantly suppressed the release of inflammatory cytokines.
UNASSIGNED: PHI ameliorated SCI-induced neuroinflammation by modulating the TLR4/MYD88/NF-κB signaling pathway. PHI has the potential to be administered as a treatment for SCI and represents a novel candidate drug for addressing neuroinflammation mediated by microglial cells.
UNASSIGNED: We demonstrated that PHI is a potential drug candidate for the therapeutic management of SCI with promising developmental and translational applications.

UNASSIGNED: Psoriasis is an immune-mediated chronic inflammatory disease. Qingre Lishi Decoction (QRLSD) has achieved great clinical effect in the treatment of psoriasis. However, the potential bioactive components and the mechanisms are yet unclear.
UNASSIGNED: To analyze the serum parameters of rats fed with QRLSD, screen out the active components of QRLSD, and explore the potential targets and pathway of QRLSD in the treatment of psoriasis.
UNASSIGNED: The active components of serum containing QRLSD were analyzed using ultra-high performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS). The targets of QRLSD in the treatment of psoriasis were predicted by network pharmacology and molecular docking. In vitro experiments verified the underlying mechanism.
UNASSIGNED: By UPLC-Q-TOF/MS, 15 prototype components and 22 metabolites were identified in serum containing QRLSD. Subsequently, 260 chemical composition targets and 218 psoriasis targets were overlapped to obtain 23 intersection targets, including LGALS3, TNF, F10, DPP4, EGFR, MAPK14, STAT3 and others. TNF, IL-10, GAPDH, STAT3, EGFR, ITGB1, LGALS3 genes were identified as potential drug targets in the PPI network analyzed by CytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that QRLSD may improve psoriasis by regulating immune and inflammatory pathways, the cytokine mediated signal transduction pathways and other signaling pathways. Molecular docking results showed that the main active components of the serum containing QRLSD had higher affinities for TNF and LGALS3. In vitro experiments confirmed that QRLSD may decrease levels of inflammatory cytokines by suppressing the NF-κB signaling pathway activated by TNF-α in human keratinocytes.
UNASSIGNED: This study explores the potential compounds, targets and signaling pathways of QRLSD in the treatment of psoriasis, which will help clarify the efficacy and mechanism of QRLSD.

Arsenic is a toxic metal-like element widely used in the pesticide, preservative and semiconductor industries. However, accumulation of arsenic through the food chain can cause serious damage to animal and human health. However, the toxic mechanism of arsenic-induced hepatotoxicity in chickens is not clear, and the present study aimed to investigate the potential role of cGAS-STING and NF-κB pathways on inflammatory injury in chicken liver. In this study, 75 white-feathered broilers were divided into a control group, a low-dose arsenic group (4 mg/kg) and a high-dose arsenic group (8 mg/kg) to investigate the toxic effects of arsenic on chicken liver. In this study, we found that pathological changes such as inflammatory cell infiltration and vesicular degeneration occurred in the liver when exposed to ATO. Crucially, exposure to ATO triggered the cGAS-STING pathway and markedly raised the levels of mRNA and protein expression of cGAS, STING, TBK1, and IRF7. The type I interferon response was also triggered. Simultaneously, STING induced the activation of the conventional NF-κB signaling pathway and stimulated the expression of genes associated with inflammation, such as IL-6, TNF-α and IL-1β. In summary, the induction of inflammatory responses via cGAS-STING and NF-κB signaling pathways under high ATO exposure provides new ideas for further studies on the toxicological mechanisms of arsenic.

Vitamin D deficiency (VDD) has been found among alcoholics. However, little is known about the effect of VDD on alcoholic liver disease and the molecular mechanisms remain unclear. The aim of the current study was to evaluate whether vitamin D was deficient among patients with alcoholic fatty liver disease (AFLD) and the effect of VDD on chronic alcoholic liver injury and possible molecular mechanisms in mice. Our results found that lower 25-hydroxyvitamin D [25(OH)D] concentrations in patients with AFLD. And further analysis found that 25(OH)D is a protective factor in patients with AFLD. Mice experiments indicated that VDD can alter the composition of gut microbiota, down-regulate the protein levels of intestinal tight junction protein Occludin and E-cadherin, up-regulate the expression of inflammatory cytokines (tnf-α, il-1β, il-6, il-8, ccl2, il-10) in liver and colon tissue. And further exacerbated the protein levels of p65,P-IκB,P-p65 in alcoholic liver injury mice. In conclusion, VDD aggravates chronic alcoholic liver injury by activating NF-κB signaling pathway.

Leukocyte cell-derived chemotaxin 2 (LECT2) is linked to various immune diseases. Previously, we reported that serum LECT2 levels correlate with disease severity in atopic dermatitis (AD) patients. To investigate the role of LECT2 in AD and elucidate its potential mechanisms, we used LECT2 to treat an AD mouse model induced by 1-Chloro-2,4-dinitrobenzene (DNCB) in LECT2 knockout (KO) and wild-type (WT) mice, and an AD cell model using TNF-α/IFN-γ-induced HaCaT cells. Inflammatory factors and barrier proteins were analyzed by histology, immunohistochemistry, RT-qPCR, ELISA, and Western Blot. Activation of the NF-κB signaling pathway was evaluated by Western Blot and immunofluorescence. In the AD mouse model, LECT2 treatment increased epidermal and dermal thickness, mast cell infiltration, and downregulated barrier proteins. Inflammatory factors were increased in skin lesions and serum. In the AD cell model, LECT2 decreased barrier protein levels and increased inflammatory factor levels, enhancing NF-κB P65 nuclear translocation. These results indicate that LECT2 exacerbates AD-like responses by dysregulating the NF-κB signaling pathway, highlighting its potential as a therapeutic target for AD management.

Mastitis is a significant inflammatory condition of the mammary gland in dairy cows. It is caused by bacterial infections and leads to substantial economic losses worldwide. The disease can be either clinical or sub-clinical and presents challenges such as reduced milk yield, increased treatment costs, and the need to cull affected cows. The pathogenic mechanisms of mastitis involve the activation of Toll-like receptors (TLRs), specifically TLR2 and TLR4. These receptors play crucial roles in recognizing pathogen-associated molecular patterns (PAMPs) and initiating immune responses through the NF-κB signaling pathway. Recent in vitro studies have emphasized the importance of the TLR2/TLR4/NF-κB signaling pathway in the development of mastitis, suggesting its potential as a therapeutic target. This review summarizes recent research on the role of the TLR2/TLR4/NF-κB signaling pathway in mastitis. It focuses on how the activation of TLRs leads to the production of proinflammatory cytokines, which, in turn, exacerbate the inflammatory response by activating the NF-κB signaling pathway in mammary gland tissues. Additionally, the review discusses various bioactive compounds and probiotics that have been identified as potential therapeutic agents for preventing and treating mastitis by targeting TLR2/TLR4/NF-κB signaling pathway. Overall, this review highlights the significance of targeting the TLR2/TLR4/NF-κB signaling pathway to develop effective therapeutic strategies against mastitis, which can enhance dairy cow health and reduce economic losses in the dairy industry.