Search Results (2,074)

Porphyromonas gingivalis (P. gingivalis), a key periodontal pathogen, has been linked to atherosclerosis development. The clinical failure of antibiotics to improve cardiovascular outcomes necessitates alternative explanations. This study examines how sub-inhibitory concentrations of metronidazole affect the biogenesis and pathogenic potential of P. gingivalis extracellular vesicles (EVs) on human umbilical vein endothelial cells (HUVECs). EVs were isolated from both untreated bacteria (N-EVs) and those treated with sub-inhibitory concentrations of metronidazole (M-EVs) through ultracentrifugation. Characterization included transmission electron microscopy (TEM), nanoparticle tracking analysis, and Western blotting for virulence factors. HUVECs were evaluated using viability, migration, cell death assays, ROS detection, NF-κB activation imaging, and cytokine measurement. Sub-inhibitory concentrations of metronidazole increased EV production by 2.3-fold and enriched M-EVs with virulence factors (lipid A LPS, Kgp, RgpA). M-EVs demonstrated significantly stronger cytotoxicity, causing greater impairment of HUVEC viability and migration, alongside increased cell death. Mechanistically, M-EVs induced elevated mitochondrial and cellular ROS, promoting NF-κB activation and enhancing secretion of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Sub-inhibitory concentrations of metronidazole exacerbate endothelial injury by amplifying EV production and virulence factor loading in P. gingivalis, offering a mechanistic explanation for the limited cardiovascular benefits of antibiotic therapy in periodontitis patients. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, typically diagnosed at an advanced stage. The identification of prodromal symptoms could support earlier detection. Among these, depression is frequently reported, raising the question of whether it may represent not only a reactive response but also a paraneoplastic manifestation. Methods: We conducted a narrative review of clinical, epidemiological and biological literature published between 1988 and 2025. Searches were performed in PubMed/MEDLINE, Scopus, and Web of Science using predefined keywords related to pancreatic cancer, depression, prodromal symptoms, cytokines, and the kynurenine pathway. Eligible studies included clinical cohorts, population-based analyses, biological investigations, and case reports exploring the temporal or mechanistic link between depression and PDAC. Results: A substantial proportion of patients (10–20%) exhibit depressive symptoms in the months preceding the clinical diagnosis of pancreatic cancer. In several cases, depression occurs independent of weight loss and new-onset diabetes. Biological evidence highlights the involvement of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), NF-κB signaling, and activation of the tryptophan–kynurenine pathway (IDO), suggesting a link between tumor-related processes and mood alterations. These mechanistic findings are actually hypothesis-generating, deriving mainly from small clinical cohorts and preclinical models. Clinically, depression is associated with reduced adherence to treatment, poorer quality of life, and shorter survival. However, no specific depressive phenotype has been identified. Conclusions: Depression may represent a potential prodromal symptom of pancreatic cancer, reflecting systemic biological processes as well as psychological reactions. Its utility as a standalone marker remains limited; future studies should integrate psychiatric, clinical and biological biomarker assessments to enhance early clinical diagnosis. Full article

Background/Objectives: Recurrent oral ulceration (ROU) is the most prevalent disorder of the oral mucosa, affecting approximately 20% of the global population. Current therapies are limited by adverse effects and high recurrence rates. Ai-Fen, enriched in the anti-inflammatory monoterpenoid L-borneol (54.3% w/w), exhibits therapeutic potential but suffers from poor aqueous solubility and low bioavailability. This study aimed to improve the physicochemical properties and in vivo efficacy of Ai-Fen through the preparation of solid dispersions. Methods: Ai-Fen solid dispersions (AF-SD) were prepared by a melt-fusion method using polyethylene glycol 6000 (PEG 6000) as the carrier. An L₉(3³) orthogonal design was employed to optimize three critical parameters: drug-to-carrier ratio, melting temperature, and melting duration. The resulting dispersions were systematically characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), and Fourier-transform infrared spectroscopy (FTIR). A chemically induced ROU model in rats (n = 8 per group) was established to evaluate the effects of AF-SD on ulcer area, serum inflammatory cytokines (TNF-α, IL-6), vascular endothelial growth factor (VEGF) levels, and histopathological outcomes. Results: The optimal formulation was obtained at a drug-to-carrier ratio of 1:2, a melting temperature of 70 °C, and a melting time of 5 min. Under these conditions, L-borneol release increased 2.5-fold. DSC and PXRD confirmed complete conversion of Ai-Fen to an amorphous state, while FTIR revealed a 13 cm⁻¹ red shift in the O-H stretching band, indicating hydrogen-bond formation. In vivo, AF-SD reduced ulcer area by 60.7% (p < 0.001) and achieved a healing rate of 74.16%. Serum TNF-α and IL-6 decreased by 55.5% and 49.6%, respectively (both p < 0.001), whereas VEGF increased by 89.6% (p < 0.001). Histological analysis confirmed marked reduction in inflammatory infiltration, accelerated re-epithelialization (score 2.50), and a 5.9-fold increase in neovascularization. Conclusions: AF-SD markedly enhanced the bioavailability of Ai-Fen through amorphization and accelerated ROU healing, likely via dual mechanisms involving suppression of nuclear factor kappa-B (NF-κB)-mediated inflammation and promotion of angiogenesis. This formulation strategy provides a promising approach for modernizing traditional herbal medicines. Full article

Uterine Fibroids (UFs) are the most common benign tumors in women of reproductive age, affecting ~77% of women overall and are clinically manifest in ~25% by age 45. Bromodomain and extra-terminal domain (BET) proteins play key roles in epigenetic transcriptional regulation, influencing many biological processes, such as proliferation, differentiation, and DNA damage response. Although BET dysregulation contributes to various diseases, their specific role in the pathogenesis of UFs remains largely unexplored. The present study aimed to determine the expression pattern of BET proteins in UFs and matched myometrium and further assess the impact of BET inhibitors on UF phenotype and epigenetic changes. Our studies demonstrated that the levels of Bromodomain-containing protein (BRD)2 and detection rate of BRD4 were significantly altered in UFs compared to matched myometrium, suggesting that aberrant BET protein expression may contribute to the pathogenesis of UFs. To investigate the biological effects of BET proteins, two small-molecule inhibitors, JQ1 and I-BET762, were used to assess their impact on UF cell behavior and transcriptomic profiles. Targeted inhibition of BET proteins markedly reduced UF cell viability compared with myometrial cells and induced cell cycle arrest. Unbiased transcriptomic profiling coupled with bioinformatic analysis revealed that BET inhibition altered multiple biological pathways, including G2M checkpoint, E2F targets, mitotic spindle, mTORC1 signaling, TNF-α signaling via NF-κB, and inflammatory response, as well as reprogrammed the UF cell epigenome. Notably, BET inhibition decreased the expression of several genes encoding extracellular matrix (ECM) proteins, a hallmark of UFs. Collectively, these results support that BET proteins play a pivotal role in regulating key signaling pathways and cellular processes in UFs. Targeting BET proteins may therefore represent a promising non-hormonal therapeutic strategy for UF treatment. Full article

In agricultural production, Deoxynivalenol (DON) generally exists and contaminates wheat, corn, and other grains, causing intestinal damage and immunotoxicity. Lycopene (LYC), an antioxidant, anti-inflammatory carotenoid, is mainly found in red fruits such as tomatoes and has been investigated for its great medicinal advantages. This study aimed to investigate the protective effect of LYC against DON-induced enterotoxicity. Our findings demonstrated that incubation of IPEC-J2 cells with 0.5 μM DON for 24 h caused intestinal barrier impairment and oxidative stress induction, which subsequently led to increased secretion of pro-inflammatory factors (TNF-α, IL-1β, IL-18, and IL-6) and decreased secretion of the counterregulatory factor (IL-10). Furthermore, DON ultimately induced NLRP3 inflammasome activation through the stimulation of the MAPK/NF-κB pathway. It is worth mentioning that the above changes were reversed after adding 30 μg/mL of LYC to DON-exposed IPEC-J2 cells. In addition, further experiments confirmed that ERK activator (4-Methylbenzylidene camphor, 4-MBC) eliminated the positive effect of LYC on alleviating enterotoxicity induced by DON in IPEC-J2 cells. In addition, further experiments confirmed that 4-MBC eliminated the positive effect of LYC on alleviating enterotoxicity induced by DON. In general, our study certified that ERK is a therapeutic target for LYC protecting DON-induced intestinal barrier dysfunction and NLRP3 inflammasome activation. Full article

Post-COVID cardiac complications have emerged as a significant and persistent clinical concern, yet their underlying mechanisms remain poorly understood. Animal models can act as proxies to investigate the pathophysiology of the human, post-acute sequelae of SARS-CoV-2 infection (PASC). The aim of this experimental study was to evaluate the expression of inflammatory biomarkers in cardiac tissue 28 days after SARS-CoV-2 infection in a female hACE2 mouse model, with a focus on chemokine-mediated immune activation. Twelve female C57BL/6 hACE2 mice were infected with the Omicron variant (BA.1.17 lineage) of SARS-CoV-2, and eleven non-infected mice served as controls. Cardiac tissue was analyzed via Western blot for markers of innate immune activation (TLR4, MyD88, NF-κB) and pro-inflammatory cytokines (IL-6, IL-18, IL-1β, TNF-α, CD11d). Cardiac tissue injury markers (iNOS, PAI-1 and Connexin43) were also analyzed. Compared to non-infected mice, cardiac tissue from infected mice showed significantly higher expression of IL-6 (p = 0.028), indicating an inflammatory state, and CD11d (p = 0.016), suggesting an inflammatory stage accompanied by sustained activation of chemokine-mediated inflammatory signaling. No significant differences in TLR4 (p = 0.340), MyD88 (p = 0.410), NF-κB p65 (p = 0.780), IL-18 (p = 0.548), IL-1β (p = 0.455), and TNF-α (p = 0.125) expressions were observed Similarly, no changes in cardiac damage markers (iNOS: p = 0.4684; PAI-1: p = 0.5345; Connexin 43: p = 0.2879) were found. The results of this experimental study would support the hypothesis of persistent low-grade inflammation as a contributor to post-COVID cardiac sequelae in females that is not accompanied by severe tissue damage, as also observed in clinical studies. This study also reinforces the need for studies evaluating the functional and structural evolution of the myocardium after an acute SARS-CoV-2 infection. Full article

Natural alkaloids derived from edible and medicinal plants have recently gained attention as bioactive molecules capable of modulating neuroinflammatory processes. Arecoline, the major alkaloid constituent of Areca catechu L. (betel nut), is well known for its cholinergic actions, yet its direct regulatory influence on microglial immune signaling has remained uncertain. In this study, murine BV2 microglial cells were employed to investigate whether arecoline could counteract lipopolysaccharide (LPS)-induced neuroinflammatory responses. Parameters including cell viability, nitric oxide (NO) production, cytokine secretion, and gene expression were assessed, and mechanistic analyses were focused on the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways. Non-toxic doses of arecoline (10–40 μmol/L) markedly decreased NO accumulation and reduced the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β). Western blot analysis further showed that arecoline suppressed LPS-activated microglial signaling by down-regulating TLR4, inhibiting NF-κB p65 phosphorylation, and limiting PI3K/AKT activation. Collectively, these data reveal that arecoline exerts immunomodulatory and neuroprotective effects through dual signaling regulation in microglia and may serve as a useful pharmacological tool or structural reference for elucidating microglial inflammatory regulation and for guiding the exploration of safer bioactive compounds. Full article

Treating acute lung injury (ALI) presents significant challenges due to adverse drug reactions. This study systematically explored the protective effects and mechanisms of a flavonoid-rich extract from Bombyx batryticatus (FBB), a traditional Chinese medicine, in combating ALI. Through UPLC-MS/MS analysis, we identified 163 flavonoid components in FBB for the first time, including flavonoids, flavonols, and chalcones. Unlike single-component flavonoid therapies, FBB provides synergistic regulation across multiple targets and pathways. Network pharmacology predictions, supported by experimental validation, revealed that FBB primarily suppresses the expression of inflammatory factors (IL-1β, IL-6, TNF-α) and oxidative stress markers (iNOS, COX-2) by modulating the PI3K/Akt, MAPK, and NF-κB signaling pathways. FBB inhibits pro-inflammatory responses and upregulates chemokine receptors like Ccr1 and Ccr2, along with IL-2Rb, at the transcriptional level. This suggests its potential to promote inflammation resolution and tissue repair through immune microenvironment remodeling, rather than mere immunosuppression. Additionally, FBB demonstrated significant anti-apoptotic effects both in vitro and in vivo, effectively reducing pulmonary edema and vascular permeability. Its complex composition and multi-pathway synergistic mechanisms offer broader regulatory potential and unique therapeutic advantages in treating ALI compared to single flavonoid compounds or conventional hormone drugs like dexamethasone (DEX). This study reveals a novel mechanism by which FBB, a multi-component natural drug, exerts therapeutic effects in ALI, providing a theoretical and experimental foundation for developing flavonoid-based compound preparations from traditional Chinese medicine. Full article

Background: Gut dysbiosis is implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH) caused by diets rich in advanced glycation end products (AGEs). European bilberry extract (EBE) exerts a regulatory effect on gut microbiota. Nevertheless, it is still unknown whether EBE influences NASH via gut microbiota and their metabolites. This study aimed to investigate the effects and underlying mechanisms of EBE on NASH caused by a long-term AGEs diet. Methods: Rats fed with a high-AGE diet were orally administered with EBE for 80 weeks, and NASH was measured. 16S rRNA analysis and targeted metabolomics were used to detect gut microbiota and SCFA, respectively. The hepatic expression of SCFA receptors and that of the HMGB1/RAGE/NF-κB signaling pathway were detected to investigate the possible molecular mechanism. Results: EBE reduced the accumulation of AGEs in the circulation and liver of high-AGE diet-fed rats. EBE also ameliorated impaired glucose tolerance and insulin sensitivity, liver inflammation, steatosis, fibrosis, and dysfunction in high-AGE-fed rats. EBE reshaped high-AGE diet-induced gut dysbiosis by increasing short-chain fatty acid (SCFA)-producing bacteria and SCFA levels and reducing deleterious bacteria. Mechanistically, EBE promoted the activation of GPR43 and inhibited the activation of downstream HDAC3 and HMGB1/RAGE/NF-κB signaling pathway in the liver of high-AGE diet-fed rats. Additionally, EBE decreased the levels of TNF-α, IL-1β, and IL-6 and increased the level of IL-10 in the liver of high-AGE diet-fed rats. Conclusions: EBE promoted the production of SCFA, which might engage with the GPR43 receptor and inhibited the activation of HDAC3 and HMGB1/RAGE/NF-κB signaling pathway, ultimately alleviating NASH caused by a high-AGE diet. Full article

Exocarpium Citri Grandis (ECG) is a distinctive medicinal and edible product originating from southern China and is often covered with a layer of characteristic “white frost” (WF). This study investigated the composition, formation mechanism, microbial safety, and anti-inflammatory activity of the WF. Multi-technique analyses revealed that WF mainly consisted of crystalline naringin (~80% of total mass). Drying-induced shrinkage and rupture of oil glands on ECG suggested metabolite migration and surface crystallization as the key mechanisms for WF formation. Microbial profiling revealed no significant differences in fungal and bacterial communities between WF and non-frost (NF) samples, and none of eight common mycotoxins was detected, confirming its microbial safety. Brewing tests demonstrated that water boiling for 30 min achieved efficient extraction of naringin, with higher yields in WF samples than in NF samples. In RAW264.7 cells, both WF and NF extract significantly inhibited lipopolysaccharide-induced NO production as well as the secretion and transcription of TNF-α, IL-6, IL-1β, iNOS, and NF-κB, with WF extract showing a stronger effect. Overall, these findings indicate that WF originates from endogenous flavonoid crystallization rather than microbial contamination and enhances the anti-inflammatory activity. This study provides a scientific basis for quality evaluation, processing optimization, and standardization of ECG products. Full article

Natural ingredients with soothing and skin-protecting effects are becoming increasingly popular in cosmetic science. Great interest has been directed to birch sap, a nutrient-rich fluid from Betula species. This study aimed to investigate whether birch sap can modulate inflammatory responses and maintain skin barrier functions in both cell and animal models. The polysaccharide composition of birch sap was characterized. TNF-α/IFN-γ-stimulated HaCaT keratinocytes were used to assess the effects of birch sap on inflammatory cytokine expression and activation of MAPK and NF-κB signaling pathways. An in vivo model of chemically induced skin irritation was further used to examine the effects of oral birch sap administration on skin hydration, transepidermal water loss, histological features, and cutaneous blood flow. Birch sap significantly reduced IL-1β, IL-6, and IL-8 expression and attenuated MAPK and NF-κB phosphorylation. In vivo, birch sap improved hydration, reduced transepidermal water loss, epidermal thickening and erythema, and decreased elevated skin blood flow associated with inflammation. These results demonstrate that birch sap provides modulatory effects on inflammation and barrier-supportive effects in both cellular and animal models, suggesting its potential as a naturally derived cosmetic ingredient for promoting skin comfort and maintaining epidermal barrier integrity. Full article

Gintonin-enriched fraction (GEF), a bioactive glycolipoprotein derived from Panax ginseng is known for its potential as a natural anti-inflammatory agent. Keratinocytes are closely related to the development and progression of various inflammatory skin conditions. However, the effect of GEF on inflammation-related responses in keratinocytes remains unclear. This study aimed to investigate whether GEF modulates key inflammatory responses in keratinocytes stimulated by tumor necrosis factor (TNF)-α. The effect of GEF on biological activities in TNF-α-stimulated keratinocytes (HaCaT cells) was evaluated using water-soluble tetrazolium salt, enzyme-linked immunosorbent, immunostaining, and immunoblotting assays. In TNF-α-stimulated HaCaT cells, GEF attenuated reactive oxygen species production, nitric oxide release, and inducible nitric oxide synthase expression. Moreover, GEF reduced the release of interleukin (IL)-6 and RANTES, while increasing the release of IL-10 in TNF-α-exposed HaCaT cells. Additionally, GEF treatment resulted in reduced cyclooxygenase-2 expression and prostaglandin E₂ release and inhibited TNF-α-induced translocation of nuclear factor-κB in HaCaT cells. Furthermore, TNF-α and IL-6 levels in ultraviolet B-irradiated HaCaT cells were reduced by GEF treatment. These findings indicated that GEF exerts anti-inflammatory effects on keratinocytes. This study provides a basis for the development of novel therapeutic approaches for the prevention and treatment of inflammatory skin disorders. Full article

Chronic inflammatory skin diseases and neurodegenerative disorders share overlapping genetic, immunologic, and metabolic pathways that may predispose individuals to cognitive decline. This review synthesizes current human genomic, transcriptomic, and bioinformatic evidence linking psoriasis, rosacea, atopic dermatitis, and bullous pemphigoid with Alzheimer’s and Parkinson’s disease. Literature from PubMed, IEEE Xplore, and Google Scholar was examined, prioritizing studies integrating genomic, transcriptomic, and proteomic analyses. Among inflammatory dermatoses, psoriasis exhibits the strongest overlap with dementia genetics, with shared susceptibility loci including APOE, IL12B, and HLA-DRB5, and transcriptional regulators such as ZNF384 that converge on IL-17/TNF signaling. Rare-variant and pleiotropy analyses further implicate SETD1A and BC070367 in psoriasis–Parkinson’s comorbidity. Rosacea demonstrates upregulation of neurodegeneration-related proteins SNCA, GSK3B, and HSPA8, together with shared regulatory hubs (PPARG, STAT4, RORA) driving NF-κB/IL-17/TNF-dependent inflammation. In atopic dermatitis, rare FLG variants interacting with BACE1 suggest a mechanistic bridge between barrier dysfunction and amyloidogenic processing. Bullous pemphigoid reveals an HLA-DQB1*03:01-mediated immunogenetic link hypothesis and cross-reactive autoantibodies targeting BP180 (collagen XVII) and BP230, highlighting an autoimmune route of neurocutaneous interaction. Other inflammatory and neurodegenerative diseases with currently weak or limited genetic evidence are also discussed, as they may represent emerging biological pathways or potential therapeutic targets within the skin–brain connection in the future. The aim of this work is to help clarify these genetic links and to advocate for the routine cognitive assessment of affected patients, enabling early detection, improved long-term quality of life, and the potential for timely therapeutic intervention. Full article

Intestinal health is critical for nutrient absorption and disease resistance in cultured fish. Yet, the effects of dietary Eucalyptus-derived biochar on the gut of largemouth bass (Micropterus salmoides) remain largely unexplored. This study evaluated whether supplementing diets with Eucalyptus biochar c profiles. In a 56-day feeding trial, M. salmoides were offered a standard diet containing either 0% (control) or graded levels of biochar. Juvenile fish (initial body weight 13.34 g) were randomly distributed into six groups with three replicates each (30 fish per replicate). Six extruded diets were formulated with 0, 2.5, 5.0, 10.0, 20.0, or 40.0 g kg⁻¹ of biochar, designated G0 through G5. Biochar had no significant effects on villus length, muscle layer thickness, villus width, or the activities of trypsin, amylase, and lipase, though goblet cell number was significantly higher in G5. mRNA expression of Claudin-3 and IL-10 was significantly upregulated in G1–G4, while IL-1β was significantly downregulated in G4 and G5, and TNF-α expression was reduced in G2 and G3. 16S rDNA sequencing showed increasing trends in the relative abundance of Firmicutes (43% to 49.17%) and Lactococcus (0% to 1.10%) in G3, accompanied by decreases in Proteobacteria and Klebsiella. Metabolomic analysis indicated significant upregulation of taurochenodeoxycholic acid-7-sulfate, apigenin, genistein, baicalein, taurocholic acid-3-sulfate, taurochenodeoxycholic acid-3-sulfate, and arginylmethionine in G3, whereas etoxazole and soyasaponin were significantly reduced. Dietary inclusion of 10 g kg⁻¹ Eucalyptus biochar improved intestinal health in largemouth bass by shaping the gut microbiota, promoting isoflavone biosynthesis and bile acid and amino acid metabolism, inhibiting the NF-κB pathway, and reinforcing the intestinal barrier. Full article

Acute liver injury (ALI) involves complex pathogenesis and lacks effective clinical therapies. Although mesenchymal stem cells (MSCs) demonstrate therapeutic potential, the role and mechanisms of adipose-derived mesenchymal stem cells (ADSCs) from Luopan Mountain pigs remain unclear. This study assessed the therapeutic potential of Luopan Mountain pig ADSCs in a D-GalN-induced rat model of ALI and investigated its association with the TLR4/MyD88/NF-κB axis. Results showed that ADSCs transplantation significantly improved liver function (by reducing ALT, AST, and TBIL levels and increasing ALB levels) and alleviated histopathological damage in liver tissue. Mechanistically, ADSCs conferred multi-faceted hepatoprotection via inhibition of the TLR4/MyD88/NF-κB axis, synergistically downregulating proinflammatory factors (TNF-α, IL-1β, IL-6, IL-8), enhancing antioxidant enzyme activity (SOD, GSH-PX), and promoting the expression of the hepatocyte regeneration marker Ki67. We demonstrate for the first time that Luopan Mountain pig ADSCs synergistically repair acute liver injury by inhibiting the TLR4/MyD88/NF-κB pathway, offering novel insights for cell therapy in ALI. Full article