Search Results (1,593)

Toll-like receptor 7 (TLR7) agonism offers a promising avenue for antiviral intervention. This study characterizes AXC-715, a novel small-molecule agonist that selectively targets TLR7 to elicit broad-spectrum antiviral effects. Structural analysis of the AXC-715–hTLR7 complex (PDB ID: 5GMH) elucidates the molecular basis of receptor activation. AXC-715 occupies the interface of TLR7 monomers, establishing critical hydrogen bonds with D555 and T586, alongside π-π and π-alkyl interactions with F408, V381, and L557. These interactions effectively promote and stabilize the active TLR7 dimeric conformation. Functionally, AXC-715 activates NF-κB signaling in a P65-dependent manner without inducing cytotoxicity in PK-15 or THP-1 cells. In vitro assays demonstrated that AXC-715 potently inhibits the replication of both pseudorabies virus (PRV) and vesicular stomatitis virus (VSV) by specifically impairing viral replication, distinct from adsorption, entry, assembly, or release processes. The antiviral effect was abolished in TLR7-knockout PK-15 cells, confirming the strict dependence of AXC-715 on on-target TLR7 signaling. These findings highlight AXC-715 as a potent TLR7 agonist that stabilizes receptor dimerization to inhibit viral replication, providing a valuable framework for developing TLR7-based antiviral therapeutics. Full article

Type 1 diabetes (T1D) is an immune-mediated disease characterized by progressive autoimmune destruction of pancreatic β cells. Although traditionally viewed as primarily T-cell-driven, B cells play essential roles in disease pathogenesis. In addition to producing islet autoantibodies, B cells contribute to immune activation through antigen presentation and cytokine secretion, thereby shaping autoreactive T-cell responses. The earliest clinical predictor of T1D is the appearance of islet autoantibodies in the blood, reflecting a breach in B-cell tolerance well before symptomatic disease onset. In individuals at high genetic risk, type I interferon (IFN) signatures are detectable in peripheral blood prior to seroconversion, suggesting that type I IFNs may act as upstream regulators of B-cell tolerance. Peripheral tolerance is enforced through layered checkpoints including transitional selection, maintenance of anergy, germinal center regulation, and regulatory B-cell differentiation. Studies in systemic autoimmunity demonstrate that type I IFN signaling lowers B-cell activation thresholds, enhances BCR and TLR responsiveness, promotes survival of autoreactive transitional clones via BAFF induction, destabilizes anergy, and skews differentiation toward inflammatory phenotypes such as T-bet+ age-associated B cells. Consistent with this model, single-cell transcriptomic and BCR repertoire analyses in T1D reveal clonal expansion and proinflammatory signatures in islet-reactive B cells during the preclinical stage. Together, these findings implicate the IFN–B-cell axis as a potential target for early disease modification. Full article

Serglycin (SRGN) has been found overexpressed and secreted in glioblastoma (GBM), associated with tumorigenic signaling and poor prognosis. In this study, we aimed to elucidate the involvement of SRGN in the unfolded protein response (UPR), an oncogenic signaling pathway implicated in protein recycling and cell fate. Herein, we developed stably transduced LN-18^shSCR GBM cells, expressing high levels of SRGN, and SRGN-depleted LN-18^shSRGN cells. We observed significantly attenuated expression and activity of all UPR mediators upon SRGN suppression, in particular PERK, IRE1, ATF6 and downstream effectors. SRGN-expressing cells possessed a constitutively active UPR, as indicated by its active phosphorylation status and accumulated pool of nuclear ATF4 in LN-18^shSCR cells. Constitutive activation of the caspase-dependent apoptotic pathway was apparent in LN-18^shSRGN cells. Induction of endoplasmic reticulum (ER) stress pointed out that LN-18^shSRGN cells were predisposed to ER stress-associated cell death, whereas LN-18^shSCR cells activated adaptive UPR signaling and displayed resistance to apoptosis. The evaluation of TLRs, TNFRs, ILs and NF-kB also underscored that SRGN is essential for their expression and active inflammatory signaling. We concluded that SRGN-expressing cells acquire a pro-survival UPR mechanism, highlighting the novel regulatory role of SRGN in the adaptation and survival of GBM cells. Full article

Rotator cuff tendon injury (RCTI) is aggravated by the pro-inflammatory milieu elicited by TLR4 and TREM1 signaling. Hence, tendon tissue engineering approaches require considerations that address these inflammatory episodes to benefit active regenerative responses. The objective of this study was to engineer and evaluate the immunocompatibility of a tendon-mimetic hydrogel composed of a chitosan–polyvinyl alcohol (PVA) blend incorporated with Collagen-I and to assess LR12 delivery for addressing TREM1-driven inflammation in RCTI management. A chitosan–PVA-HEMA-Acrylic acid (CPHA) hydrogel was synthesized by blending the linear natural polysaccharide chitosan and linear synthetic polymer PVA in an aqueous phase, followed by incorporation and redox chain growth with HEMA using acrylic acid (AA). Interpenetration of Collagen-I in CPHA yielded the CPHA-C hydrogel. CPHA and CPHA-C hydrogels displayed ample surface functional moieties provided by the co-polymers, exhibited excellent porosity as revealed by SEM imaging (28.65 ± 6.85 and 41.56 ± 18.00, respectively, for CPHA and CPHA-C), and were amphiphilic, as evident by contact angle analysis (~70 for CPHA and CPHA-C). Both hydrogels displayed a progressive release profile for the TREM1-inhibitory peptide LR12 for 7 days, whereas the LR12-loaded CPHA hydrogel exhibited increased TREM1 inhibition in LPS-challenged RAW264.7 macrophages. CPHA and CPHA-C hydrogels were immunocompatible and masked the oxidative damage in RAW264.7 macrophages, as evident by decreased levels of mitochondrial superoxide and ROS. Additionally, the CPHA hydrogel displayed an increased TGFβ/TLR4 ratio (0.24), whereas the CPHA-C (−0.52) system showed a decreased ratio upon exposure to tenocytes and macrophages. Overall, the findings highlight the potential of CPHA and CPHA-C hydrogels as candidates for tendon regenerative applications. Full article

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder with a high incidence of anxiety and depression. However, the underlying mechanisms of these symptoms remain to be fully elucidated. This study investigated the effects and mechanisms of a 20% ethanolic extract of Petasites japonicus leaves (EPJ) on dextran sulfate sodium (DSS)-induced colitis and depression-like behaviors. The physiological compounds identified in the EPJ were citric acid, chlorogenic acid, caffeic acid, fukinolic acid, 3,5-dicaffeoylquinic acid, quercetin 3-O-β-D-glucose-6″-acetate, 4,5-dicaffeoylquinic acid, kaempferol-3-O-(6″-acetyl)-β-glucopyranoside, and pedunculoside. EPJ significantly alleviated DSS-induced colitis, as evidenced by improvements in body weight loss (87.41% vs. 76.02% in the DSS group), colon length (5.75 vs. 4.34 cm), intestinal permeability (52.80 vs. 163.01 μg/mL), and myeloperoxidase (MPO) activity (0.24 vs. 0.67 U/mg) (p < 0.05). Histological analysis further confirmed recovery of goblet cells and attenuation of muscle layer thickening. EPJ also reversed DSS-induced gut microbiota dysbiosis and contributed to the restoration of microbial homeostasis. Behavioral assessments showed that EPJ effectively ameliorated depression-like behaviors. EPJ improved antioxidant systems in colon and brain tissues by modulating malondialdehyde (MDA) levels and reduced glutathione (GSH) and superoxide dismutase (SOD) activity. EPJ further upregulated tight junction protein expression and suppressed TLR4/NF-κB inflammatory pathway activation in both colon and brain tissues. Moreover, EPJ modulated serum stress-related hormones, normalized hypothalamic–pituitary–adrenal (HPA) axis dysregulation, regulated the BDNF/TrkB signaling pathway, and modulated tryptophan–kynurenine metabolism. Collectively, these findings suggest that EPJ exerts protective effects against DSS-induced colitis and depression-like behaviors. Full article

Tumor microenvironments, particularly hypoxia and inflammation, heavily influence colorectal cancer (CRC) pathogenesis by altering polyamine metabolism. Identifying natural compounds targeting these vulnerabilities remains critical. Integrating untargeted metabolomics, network pharmacology, and a human endogenous metabolite library screen, we identified apigenin (API) as a potent anti-CRC candidate. API significantly inhibited the proliferation, migration, and invasion of RKO and HCT116 cells in vitro and suppressed xenograft tumor growth in vivo. Crucially, high-throughput screening revealed that polyamines rescued CRC cells from API-induced cytotoxicity. Mechanistically, API exerts its effects by dismantling a newly identified HIF-1α/SMOX positive feedback loop. In CRC, HIF-1α transcriptionally activates spermine oxidase (SMOX), while SMOX-driven polyamine metabolism fuels the TLR4/MyD88 inflammatory cascade to continuously stabilize HIF-1α. API acts as a “circuit breaker” for this axis, significantly reducing the spermidine/spermine ratio and downregulating inflammatory signaling. Ultimately, API effectively remodels polyamine metabolism and suppresses CRC progression by disrupting the HIF-1α/SMOX and TLR4/MyD88 pathways, offering a novel metabolic mechanism for API in CRC therapy. Full article

As a representative next-generation probiotic, Akkermansia muciniphila (A. muciniphila) produces a variety of functional proteins that play critical roles in the prevention and treatment of multiple diseases, including metabolic disorders, inflammatory diseases, neurological disorders, and cancer. This review summarizes the disease-associated proteins of A. muciniphila reported to date, including the outer membrane proteins Amuc_1100 and Amuc_1098, as well as the secreted proteins P9 (Amuc_1631), P5, Amuc_1409, Amuc_1434, and Amuc_2109. These proteins exert their biological effects by activating multiple signaling pathways, such as Toll-like receptor 2 (TLR2), ICAM-2, and Wnt/β-catenin, thereby regulating physiological processes including glucagon-like peptide-1 (GLP-1) secretion, serotonin biosynthesis, lipid metabolism, and intestinal stem cell proliferation. This review provides a theoretical foundation and future perspectives for in-depth research investigation and clinical application of A. muciniphila disease-related proteins. Full article

Pingyin rose essential oil (PREO) is extracted from fresh petals exclusively cultivated in Shandong Province. This PREO has been used in traditional Chinese medicine (TCM) for decades to treat skin issues like excessive oxidative stress and inflammation. The purpose of this study was to assess the impact of PREO on the inflammatory pathway in HaCaT cells produced by LPS. In vitro methods were used to ascertain the expression of inflammatory proteins, and network pharmacological analysis was employed to predict the signaling pathway. According to our findings, PREO significantly reduced LPS-induced oxidative stress, decreasing nitric oxide (NO) and reactive oxygen species (ROS) production by 42% and 38%, respectively, and malondialdehyde (MDA) levels by 35%, while enhancing superoxide dismutase (SOD) activity by 28% (p < 0.01). PREO treatment (0.1%, 18 h) markedly suppressed pro-inflammatory cytokines, with mRNA levels of TNF-α, IL-1β, IL-6, and IL-8 reduced by 52%, 47%, 45%, and 40%, respectively. Mechanistically, PREO inhibited the TLR4-NF-κB pathway, downregulating MyD88 and TRIF expression by 60% and 55%, and reducing NF-κB p65 and IκB-α phosphorylation by 50% and 48%. Network pharmacology and molecular docking identified Citronellol (54.37% of PREO) as the major bioactive component, exhibiting strong binding affinities with IKKβ (−5.7 kcal/moL) and MyD88 (−4.5 kcal/moL). This research, distinct from previous investigations on Rosa rugosa polyphenols, provides a novel mechanistic link between PREO’s traditional use and its observed anti-inflammatory and antioxidant effects in keratinocytes, specifically through inhibition of the TLR4-NF-κB pathway. Full article

Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent, but its clinical utility is limited by oxidative stress-mediated renal toxicity. This study evaluated the nephroprotective potential of the dietary polyphenolic bioactive molecule piceatannol (PIC) in its crude and liposomal nanoparticle (PIC-LNP) forms against MTX-induced kidney injury in rats. Sixty rats were allocated into six groups and received vehicle, PIC, PIC-LNPs, MTX, or combinations of MTX with PIC or PIC-LNPs. MTX administration induced marked renal dysfunction and oxidative/nitrosative stress, reflected by elevated serum urea, creatinine, and uric acid, together with increased renal ROS, MDA, protein carbonyls, 8-OHdG, and nitric oxide, in parallel with suppression of the Nrf2/HO-1 antioxidant pathway. These disturbances were accompanied by activation of TLR4/NF-κB and MAPK signaling, upregulation of pro-inflammatory cytokines, and a shift toward apoptosis, as evidenced by increased Bax and caspase-3 and reduced Bcl-2 expression. Histological and ultrastructural analyses confirmed extensive glomerular and tubular damage with mitochondrial disruption and cytoplasmic vacuolations. PIC treatment attenuated these MTX-induced alterations, whereas the liposomal formulation conferred superior protection. PIC-LNPs restored Nrf2/HO-1 signaling, enhanced endogenous antioxidant defenses, reduced oxidative/nitrosative and inflammatory responses, and normalized apoptotic markers, accompanied by substantial preservation of renal architecture and cellular integrity. Immunohistochemistry demonstrated strong Nrf2 expression with minimal NF-κB activation in the PIC-LNP group. Collectively, these findings highlight liposomal piceatannol as a promising bioactive-molecule-based strategy for controlling oxidative stress and mitigating chemotherapy-associated oxidative-stress-related renal injury. Full article

Background: Hepatic ischemia–reperfusion (I/R) injury induces systemic oxidative stress and inflammatory responses that may lead to remote lung injury. This study investigated whether taxifolin attenuates hepatic I/R-induced lung damage and examined the involvement of the nuclear factor-κB (NF-κB) and high-mobility group box-1 (HMGB1) signaling axis. Methods: Twenty-eight male Wistar rats were divided into four groups (n = 7): control, taxifolin, hepatic I/R, and taxifolin+I/R. Serum oxidative stress markers (malondialdehyde [MDA], interleukin [IL]-6, total antioxidant/oxidant status [TAS/TOS]) and wet-to-dry lung weight ratio were measured. Lung tissues were evaluated histopathologically and immunohistochemically for NF-κB and HMGB1 expression. Bioinformatics pathway enrichment and molecular docking analyses were also performed. Results: Hepatic I/R significantly increased serum MDA, IL-6, and TOS levels and decreased TAS (p < 0.05). Severe lung injury was observed in the hepatic I/R group (median score: 11), whereas taxifolin pretreatment significantly reduced the injury score (median score: 5, p < 0.001). NF-κB and HMGB1 expression were markedly elevated following hepatic I/R and significantly decreased with taxifolin treatment (p < 0.05). A strong positive correlation was found between NF-κB and HMGB1 expression (r = 0.82, p < 0.001). Pathway enrichment analysis indicated involvement of Toll-like receptor (TLR)-related inflammatory signaling, and docking analysis demonstrated favorable binding of taxifolin to TLR4 and NF-κB p65. Conclusion: Taxifolin attenuated hepatic I/R-induced lung injury by reducing oxidative stress and suppressing HMGB1–TLR4–NF-κB-mediated inflammatory signaling. Full article

This study aimed to systematically elucidate the antihyperlipidemic mechanism of paeoniflorin, and we adopted an integrated multi-omics strategy to screen the key molecular targets and regulatory pathways involved in its action, followed by experimental validation to verify the potential regulatory effects of paeoniflorin on the screened targets and metabolic processes. Rats with high-fat diet-induced hyperlipidemia received paeoniflorin treatment. Liver histopathology was evaluated using hematoxylin–eosin and Oil Red O staining. Serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bile acids, activated partial thromboplastin time, prothrombin time, thrombin time, and fibrinogen were measured using a biochemical analyzer. Integrated multi-omics analyses were performed to investigate paeoniflorin’s lipid-lowering mechanism. Critical pathways and targets identified were validated using Western blotting. Paeoniflorin alleviated pathological liver damage in hyperlipidemic rats and improved blood lipid levels, coagulation function, and liver function markers. Multi-omics analyses verified that paeoniflorin downregulated the expression of TREM-1, TLR4, NF-κB, TNF-α, and IL-1β, thereby alleviating hepatic inflammation. Paeoniflorin also upregulated the expression of low-density lipoprotein receptors (LDLR), liver X receptor alpha (LXRα), and ATP-binding cassette subfamily G member 1 (ABCG1), while downregulating proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, contributing to balanced cholesterol metabolism. Paeoniflorin normalized glycerophospholipid and branched-chain amino acid metabolism, which correlated with reduced inflammation and improved cholesterol metabolism. Paeoniflorin ameliorates hyperlipidemia through multitarget mechanisms, potentially by suppressing the TREM-1-TLR4-NF-κB signaling pathway to reduce inflammation and by regulating cholesterol metabolism via the PCSK9-LDLR and LXRα-ABCG1 pathways. Full article

Background: MSCs possess strong immunoregulatory properties and play a central role in maintaining immune homeostasis by limiting inflammatory responses. Their function is highly plastic and influenced by environmental cues, including viral signals. How SARS-CoV-2-derived antigens affect MSC immunoregulation remains incompletely understood. This study aimed to investigate the impact of SARS-CoV-2 peptides on MSC-mediated immune modulation of T-cells. Methods: MSCs were stimulated directly with SARS-CoV-2 spike protein S peptides or cocultured with SARS-CoV-2 peptide-activated T-cells. TLR4 surface expression and receptor downstream signaling were assessed to evaluate pathway activation. MSC immunoregulatory function was analyzed by measuring suppression of TNF-α and IFN-γ expression and induction of CD4⁺FOXP3⁺ regulatory T-cells. TLR4 inhibition and lipopolysaccharide (LPS) stimulation were used to examine pathway specificity and interaction. Results: SARS-CoV-2 peptides activated TLR4-associated signaling in MSCs, increasing TLR4 expression and NF-κB phosphorylation. Peptide-treated MSCs showed impaired suppression of pro-inflammatory cytokines and reduced induction of regulatory T-cells. TLR4 inhibition prevented these effects. LPS induced similar effects, while combining LPS and peptide stimulation partially restored physiological T-cell cytokine suppression. Conclusions: SARS-CoV-2 peptides modulate MSC immunoregulatory function on T-cells via TLR4-dependent mechanisms. Full article

Background: Polygonatum sibiricum (PS), a perennial herbaceous plant belonging to the Liliaceae family, is widely distributed in China and other East Asian countries. PS has been used as food and medicine for thousands of years, and its rhizomes are rich in Polygonatum sibiricum polysaccharides (PSP), which exhibit various bioactivities, yet their structural features and therapeutic mechanisms against ulcerative colitis (UC) remain unclear. Methods: A homogeneous polysaccharide, PSP-1b (57.45 kDa), was isolated from the rhizomes of PS via ion-exchange and gel filtration chromatography and structurally characterized using chromatographic and spectroscopic methods. In vivo, its effects were evaluated in a dextran sulfate sodium (DSS)-induced mouse model of UC, while in vitro mechanisms were explored using macrophages stimulated with lipopolysaccharide (LPS) and neutrophil extracellular traps (NETs). Results: PSP-1b was identified as a neutral polysaccharide with minimal branching. Its primary structural backbone was largely composed of →4)-β-D-Galp-(1→ residues. A portion of these backbone residues was substituted at the O-6 position by side chains primarily composed of β-D-Galp-(1→ units. In vivo, PSP-1b significantly alleviated DSS-induced colitis by reducing inflammatory cytokine secretion, suppressing colonic macrophage infiltration, and reversing neutrophil extracellular traps (NETs) deposition. In vitro, PSP-1b directly interacted with TLR4, inhibited the MAPK/NF-κB signaling pathway, and attenuated LPS- and NET-induced macrophage polarization and inflammation. Conclusions: PSP-1b as a promising candidate for functional foods or therapeutic agents targeting inflammatory bowel disease. Full article

Endothelial dysfunction, chronic inflammation, immune dysregulation, oxidative stress, mitochondrial dysfunction, and metabolic disturbances collectively contribute to cardiovascular diseases (CVDs) associated with blood stasis patterns. Xuefu Zhuyu Decoction (XFZYD) is widely used clinically for the management of CVDs. Based on serum-exposed prototype profiling in rats, two pharmacology-driven core component sets of XFZYD were defined as the core set for the promotion of blood circulation and the elimination of blood stasis (CPBEB; HSYA, GRo, FA, β-ECD, AMY, ALB, PF) and the core set for the regulation of qi and the relief of pain (CRQRP; LIQ, NR, NAR, ROF, HSD, NHP, LTG, NRG, ISL, FNT, NOB, PD, SSa). CPBEB primarily targets vascular pathology by regulating endothelial dysfunction with dyslipidemia-driven arterial lipid deposition. Mechanistically, CPBEB is associated with improved endothelial function, reduced plaque instability, attenuated chronic inflammation and oxidative stress, normalized lipid and bile acid metabolism, and decreased thrombosis. CRQRP primarily modulates vascular tone and systemic energy metabolism. These effects are linked to enhanced AMPK/SIRT1-driven antioxidant defenses and mitochondrial homeostasis, increased NO/cGMP signaling, coordinated crosstalk among the TLR4/NF-κB, JAK/STAT, NLRP3, and PPAR pathways, and remodeling of the gut microbiota–immune network. In summary, this review integrates modern analytical approaches with network pharmacology and the literature evidence to clarify the material basis underlying XFZYD’s therapeutic effects in CVDs, thereby supporting the modernization and internationalization of traditional Chinese medicine. Full article

Cardiovascular diseases (CVDs) remain the primary cause of human morbidity and mortality in the world. Inflammation, oxidative stress, and vascular remodeling are the key factors that make CVDs worse. The nuclear factor κB (NF-κB) signaling pathway is a major regulator in the progression of CVDs. NF-κB activates wrongly, induces the secretion of pro-inflammatory cytokines (including TNF-α, IL-6, and IL-1β), and enhances reactive oxygen species (ROS) generation. These accelerate endothelial dysfunction, myocardial damage, and atherosclerotic plaque development. Natural products are structurally diverse, multi-targeted, and low toxicity. They offer a promising way to prevent and treat cardiovascular disease by modulating the NF-κB signaling pathway. This review summarizes the recent studies about using natural products (including flavonoids, terpenoids, alkaloids, polyphenols, and polysaccharides) to treat CVDs through the NF-κB pathway, with a critical analysis of evidence strength according to CVDs indication (atherosclerosis, myocardial ischemia/reperfusion injury, pulmonary arterial hypertension, etc.) and study type (in vitro, in vivo animal, and human clinical research). We detail their molecular mechanisms, such as inhibiting the nuclear translocation of NF-κB p65, downregulating IκB phosphorylation, blocking upstream signaling (e.g., TLR4/MyD88, PI3K/Akt, MAPK), and affecting with other pathways (e.g., Nrf2/HO-1, SIRT1) to reduce inflammation and oxidative stress together. We also detail the effects of these natural products in various CVDs models, including atherosclerosis, hypertension, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, and pulmonary arterial hypertension, highlighting the characteristics of their treatments. Finally, we discuss the challenges of bringing natural products into the clinic and share some ideas to solve difficulties, with an in-depth critical analysis of the translational bottlenecks (poor bioavailability, unclear structure–activity relationships, incomplete mechanistic elucidation, and lack of large-scale clinical trials) and their underlying causes across different natural product classes. In summary, this review offers new perspectives on developing natural product-based therapies targeting the NF-κB signaling pathway for CVDs. It offers useful references for both preclinical studies and clinical applications. Full article