Search Results (1,663)

Microplastic pollution has emerged as a pervasive stressor in aquatic ecosystems, with aquatic invertebrates playing central roles in particle uptake, retention, and transfer within food webs. This review synthesises evidence on microplastic ingestion, bioaccumulation, trophic transfer, and biomagnification across major aquatic invertebrate groups, including arthropods, molluscs, sediment-associated worms, suspension feeders, and echinoderms. A structured literature search identified 66 studies spanning freshwater, estuarine, and marine environments. Evidence indicates that microplastic uptake occurs through multiple pathways, including filter feeding, deposit feeding, grazing, and predator–prey interactions. Across the reviewed studies, feeding strategy, habitat-specific exposure, and particle characteristics were recurrently associated with variation in microplastic ingestion, retention, and trophic transfer. While ingestion and bioaccumulation were widely documented, quantitative understanding of trophic transfer within aquatic invertebrate food webs remained limited, and no conclusive evidence of biomagnification was identified. To interpret recurring patterns, this review proposes the Trait–Habitat–Particle (THP) framework as a conceptual tool linking biological and functional traits, habitat-mediated exposure, and particle properties. Methodological inconsistencies, limited representation of certain taxa and habitats, and insufficient quantification of trophic transfer remain important knowledge gaps. Future research should prioritise methodological standardisation and ecologically realistic long-term studies. Full article

Fungal infections remain a major global health challenge, underscoring the need to better understand host–pathogen interactions. Extracellular vesicles (EVs) released by fungal pathogens are emerging as key modulators of immune responses. Here, we investigated how EVs from Candida albicans and Aspergillus fumigatus influence macrophage activation, focusing on the integration of pattern recognition receptors (PRRs) and cytosolic sensing pathways. EVs were characterized by nanoparticle tracking analysis, zeta potential, and cryo-electron microscopy. Human THP-1-derived macrophages were stimulated with fungal EVs, and cytokine production, gene expression, and signaling pathway activation were assessed by ELISA, RT-qPCR, and Western blotting. C. albicans EVs induced a strong pro-inflammatory response, with increased production of IL-1β, IL-6, TNF, IL-8, and IFN-β after 24 h. In contrast, A. fumigatus EVs elicited a more limited response, characterized by IL-4 production and minimal pro-inflammatory cytokine induction. Both EV populations modulated PRR expression and activated the cGAS–STING–IRF3 axis; however, C. albicans EVs promoted coordinated activation of TLR4, TLR9, and Dectin-1–CARD9 signaling, whereas A. fumigatus EVs downregulated CARD9 and dampened inflammation. These findings demonstrate that fungal EVs differentially shape macrophage responses through species-specific integration of immune sensing pathways. Full article

Crohn’s disease (CD) is a chronic inflammatory bowel disease with a rising incidence and prevalence worldwide. It is associated with Mycobacterium avium subspecies paratuberculosis (MAP). Current CD treatment strategies are based on anti-inflammatory therapies, including anti-TNF-α drugs. These treatment options provide short-term benefits and are associated with numerous side effects in CD patients. Manuka honey is distinguished from other honey by its high content of methylglyoxal (MGO). MGO, a reactive metabolite, is also generated endogenously in macrophages during infection through glycolysis; however, the amount is insufficient to neutralize the ongoing infection and subsequent tissue damage. This study examined whether exogenous, low-dose MGO can modulate MAP-driven inflammatory and glycolysis- and lactate-associated markers in infected macrophages. THP-1 macrophages were infected with the CD-associated MAP strain and then treated with MGO doses at defined time intervals. We measured markers of M1-/M2-like phenotype polarization, monocarboxylate transporters, lactate export, antioxidant responses, cytokines, and selected glycolysis- and lactate-associated markers at both the mRNA and protein levels. MGO reduced M1 signaling markers CXCL10 (p < 0.05), TNF-α (p < 0.0001), IL-1β (p < 0.01), and IL-6 (p < 0.0001). Simultaneously, MGO promoted M2 shift, elevating CD206 by 1.20-fold and IL-10 by 7-fold. Low-dose MGO administration was associated with increases in Nrf-2 (1.4-fold), HO-1 (1.4-fold), and IL-1Ra (1.5-fold), while the pro-inflammatory cytokines decreased. Metabolically, MGO downregulated MCT4 (p < 0.01) and reduced lactate export by 30%. These changes were coupled with higher PHD2 (1.4-fold) and decreases in GLUT1 (0.9-fold), PKD1 (0.8-fold), and IL-1β, consistent with attenuated glycolysis- and lactate-associated inflammatory signaling. These results suggest that hormetic concentration of MGO mitigates MAP-induced inflammatory activation while altering glycolysis- and lactate-related signaling markers in infected macrophages. Most importantly, we unraveled the predicted molecular mechanism by which MGO suppresses inflammation and modulates oxidative damage. Full article

Background/Objectives: Phenotypic drug tolerance, distinct from genetic resistance, allows Mycobacterium tuberculosis (Mtb) to survive prolonged antibiotic exposure and contributes to treatment failure and relapse. The trehalose recycling pathway, mediated by the LpqY-SugABC transporter, has been implicated as a metabolic “escape” mechanism that sustains Mtb viability under antibiotic and nutrient-limiting stress, making it an attractive target for adjunctive, tolerance-breaking therapeutics. Methods and Results: Here, we conducted a high-throughput phenotypic screen of 50,000 compounds from chemically diverse libraries, using a carbon source-restricted assay that forces Mtb to rely on trehalose uptake for growth, to identify small-molecule inhibitors of this pathway. This approach yielded 23 confirmed hits in Mtb, spanning several chemical scaffolds, including thioureas, propanamides, benzamides, and carboxamides. Using an isogenic set of Mtb wild-type, LpqY-SugABC transposon knockout, and complemented strains, we confirmed that the genetic loss of transporter loss reproduces accelerated killing by isoniazid, rifampicin, and bedaquiline, but not moxifloxacin, and that loss of trehalose recycling sensitizes mycobacteria to oxidative stress. Using orthogonal functional assays, fluorescent trehalose probe (FITC-tre) uptake inhibition and H₂O₂ hypersensitization, thiourea-containing compounds emerged as the candidates most consistent with transporter-specific activity, phenocopying the effects of genetic LpqY-SugABC loss, while biochemical assays against recombinant trehalase (Rv2402) excluded downstream enzymatic inhibition as their mechanism of action. In addition, several hits potentiated rifampicin-mediated killing of intracellular Mtb in THP-1 macrophages, in some cases reducing bacterial burden below levels achieved by monotherapy. Conclusions: These findings indicate that the trehalose recycling pathway is functionally druggable by small molecules identified through unbiased phenotypic screening and nominate thiourea- and propanamide-based scaffolds as priority candidates for further mechanistic characterization, including direct target-engagement studies, and optimization as adjunctive anti-tuberculosis agents targeting drug-tolerant Mtb populations. Full article

Cold-inducible RNA-binding protein (CIRP/CIRBP) is recognized as an extracellular damage-associated molecular pattern. However, its relationship to endothelial redox-inflammatory injury in atherosclerosis remains poorly characterized. Here, we explored the associations among CIRP, endothelial dysfunction, and TLR4-/SIRT6-related changes. In high-fat diet (HFD)-fed ApoE^−/− mice, circulating CIRP was elevated and positively correlated with atherosclerotic plaque burden. This increase coincided with systemic redox imbalance, impaired NO/eNOS activity, and vascular inflammation. In HUVECs, CIRP exposure reduced cell viability and impaired NO/eNOS function. These effects were accompanied by increased ROS accumulation and MDA content, together with reduced GSH-Px activity. CIRP also increased inflammatory cytokine production, NF-κB p65 phosphorylation, and THP-1 adhesion. At the molecular level, CIRP reduced SIRT6 expression. Overexpression of SIRT6 attenuated CIRP-induced endothelial injury, oxidative stress, and NO/eNOS dysfunction. CIRP also increased TLR4 expression. Accordingly, pharmacological TLR4 inhibition with TAK-242 attenuated CIRP-associated endothelial injury and partially restored SIRT6 expression and protein stability. Conversely, SIRT6 silencing weakened the protective effects of TAK-242. In addition, CIRP exposure was accompanied by increased overall eNOS acetylation. This increase was attenuated by TAK-242 and further enhanced by SIRT6 silencing. Exploratory cross-context transcriptomic analysis identified overlapping inflammatory and oxidative stress-related signatures. Representative antioxidant-related changes were further examined in CIRP-treated HUVECs through assessment of GPX4 and CAT mRNA expression and CAT activity. Finally, in a preliminary clinical cohort, serum CIRP levels were higher in patients with coronary heart disease and were positively associated with Gensini score, including selected exploratory multivariable models. Overall, these findings provide preliminary evidence that CIRP is associated with redox-inflammatory endothelial injury. The results are also consistent with the possible involvement of TLR4-/SIRT6-related signaling. These observations should be interpreted cautiously because of the relatively high CIRP concentration used in vitro, the cross-context transcriptomic comparison, and the small clinical cohort. Full article

Frailty and osteoarthritis (OA) frequently coexist in older adults, yet the extent to which they share molecular programs across tissues remains unclear. We integrated bulk transcriptomics, peripheral immune and OA meniscal single-cell atlases, inferred cell–cell communication, and an in vitro myeloid–chondrocyte conditioned-medium model. Frailty-associated vastus lateralis and OA synovium shared a 16-gene program enriched for inflammatory and migratory processes, which was refined by protein–protein interaction analysis into a 15-gene hub module (Hub-15). Donor-aware pseudobulk analysis showed coordinated Hub-15 upregulation in CD8 T, natural killer, B, and monocyte/macrophage-like cells, with the highest scores in monocyte/macrophage populations. In the meniscal atlas, donor-level analysis of 7 normal and 6 OA donors identified a 20.5 percentage point lower proportion of inflammatory/stress cells and a 17.3 percentage point higher proportion of fibrochondrocyte-like cells in OA (both false discovery rate = 0.010), whereas state-specific Hub-15 differences were not significant after correction. Exploratory communication analysis nominated directionally consistent candidate myeloid-to-structural signaling axes, although none remained significant after multiple-testing correction. Conditioned medium from cytokine-primed THP-1 cells elicited inflammatory and matrix-catabolic responses in C28/I2 cells. These findings identify a cross-tissue, leukocyte-shared, and myeloid-enriched inflammatory program that converges across independent frailty and OA cohorts, providing a hypothesis-generating framework for future mechanistic testing. Full article

Background. Gout is an inflammatory disease caused by the deposition of monosodium urate (MSU) crystals, leading to reactive oxygen species (ROS) production and activation of the NLRP3 inflammasome with subsequent IL-1β release. Poly-gallic acid (PGAL), enzymatically synthesized polymer, has demonstrated antioxidant and anti-inflammatory properties; however, its effect on MSU-induced inflammasome activation remains unclear. Thus, this work aims to evaluate the effect of PGAL on oxidative stress and inflammatory responses induced by MSU crystals in THP-1-derived macrophages. Methods. Macrophages were pretreated with PGAL and stimulated with MSU crystals. Cell viability, apoptosis, phagocytosis, ROS and NO production, soluble urate levels, and NLRP3 and IL-1β expression were evaluated. Molecular docking and binding free energy calculations were performed to characterize PGAL–MSU interactions. Results. PGAL significantly reduced ROS and NO production, and apoptosis. PGAL treatment also decreased MSU crystal phagocytosis and significantly reduced NLRP3 and IL-1β. Computational analysis revealed that PGAL interacts with MSU crystals predominantly through electrostatic interactions, including Na⁺ coordination and hydrogen bonding. Conclusions. PGAL attenuates MSU-induced oxidative stress and NLRP3/IL-1β activation, possibly by interfering with crystal internalization. These findings suggest a mechanism based on modulation of crystal–cell interactions and downstream inflammation responses. Full article

Chronic and diabetic wounds are characterized by persistent inflammation, excessive oxidative stress, and impaired cellular responses, collectively leading to delayed tissue repair. This study aimed to evaluate a thermoresponsive gel incorporating Aloe vera (AV) extracts and silk fibroin (SF), focusing on its biocompatibility, anti-inflammatory, antioxidant, and pro-regenerative potential. The AV: SF mixture and gel formulation were evaluated in macrophage-like THP-1 cells, and human diabetic dermal fibroblasts (HDdF) under non-induced and LPS/IL-6/TNF-α-induced inflammatory conditions. Both formulations maintained high cell viability across all cell types, indicating good biocompatibility. Under inflammatory conditions, both the AV: SF mixture and gel significantly reduced intracellular ROS levels and suppressed TNF-α and IL-1β secretion. In addition, NF-κB p65 activation was attenuated in both macrophage-like THP-1 cells and HDdF. Macrophage-like THP-1 cells displayed the M2 (CD80^low/CD206^high) phenotype, indicating modulation of macrophage polarization toward wound remodeling and repair. Overall, the AV: SF-based gel system demonstrated coordinated antioxidant, anti-inflammatory, and pro-regenerative effects in vitro. These findings support its potential as a multifunctional biomaterial for modulating inflammation-associated cellular dysfunction in chronic and diabetic wound environments. Full article

Background: Vaccinium berries are rich in polyphenolic compounds with recognized health properties; however, studies integrating phytochemical characterization with functional cellular assays remain limited. This study comparatively evaluated wild (Vaccinium myrtillus L., VM) and cultivated blueberry (Vaccinium corymbosum L., VC) using phytochemical profiling alongside in vitro antioxidant and anti-inflammatory activity testing. Six samples from Romanian regions were extracted using ultrasound-assisted methods, then analyzed for total phenolics, flavonoids, tannins, and antioxidant activity (DPPH, ABTS, FRAP, CUPRAC). Anthocyanins were further characterized by LC–MS/MS. The most bioactive extracts were tested for cytocompatibility, intracellular ROS modulation in Caco-2 cells, and anti-inflammatory activity in LPS-stimulated THP-1 cells. VM extracts showed higher total phenolic, anthocyanin contents, and antioxidant capacity than VC, with LC–MS/MS confirming a richer anthocyanin profile and differences in other phenolic compounds. Both extracts significantly reduced intracellular ROS in H₂O₂-stimulated Caco-2 cells and decreased IL-8 secretion in LPS-stimulated THP-1 cells, with a more pronounced dose-dependent anti-inflammatory effect for VM. These findings demonstrate that phytochemical differences between wild and cultivated Vaccinium species translate into distinct biological activities at the cellular level. The integrated approach provides a mechanistic link between composition and function, supporting the superior antioxidant and anti-inflammatory potential of VM and its relevance for functional food and nutraceutical applications. Full article

Tuberculosis (TB) remains a major global health challenge, compounded by rising drug resistance. Traditional medicinal plants used for TB-related symptoms represent a valuable yet underexplored source of potential antimycobacterial agents. In this study, the phytochemical content and biological activities of Dombeya rotundifolia and Lippia javanica were evaluated, and antimycobacterial compounds were isolated through bioassay-guided fractionation. Plant leaves were collected, extracted with solvents of varying polarity, and screened for phenolics and flavonoids. Antioxidant activity was assessed using DPPH and ferric reducing power assays, antimycobacterial activity was tested against Mycobacterium smegmatis, anti-inflammatory activity was determined by the egg albumin denaturation method, and cytotoxicity was evaluated in THP-1 cells using the MTT assay. Extraction yields varied, with water extracts of L. javanica showing the highest yield and hexane extracts of D. rotundifolia the lowest. Both plants contained bioactive phytochemicals with measurable antioxidant activity, while acetone and dichloromethane extracts of D. rotundifolia displayed the strongest antimycobacterial activity with MIC values of 0.16 mg/mL. Cytotoxicity assays indicated moderate toxicity at higher extract concentrations. Bioassay-guided isolation led to the identification of two fatty acid fractions with tentative characterization, which showed notable antimycobacterial activity (MIC 0.25 mg/mL). These findings provide preliminary support for the ethnomedicinal use of D. rotundifolia in respiratory conditions traditionally associated with tuberculosis and suggest a potential contribution of its fatty acids to its observed antimycobacterial activity. Full article

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health burden. Host genetic factors play a critical role in TB susceptibility, but the underlying mechanisms are not fully understood. Genome-wide association studies have identified DUSP14 as a TB susceptibility gene, and the single nucleotide polymorphism (SNP) rs1051838 in DUSP14 seems to be associated with TB risk. Using in vitro models including THP-1-derived macrophages, A549 cells, and HEK293T cells, we investigated how rs1051838 regulates DUSP14 expression and modulates macrophage responses to Mtb infection. We found that the G allele of rs1051838 exhibits higher transcriptional activity than the A allele in reporter assays. The G allele creates a CpG dinucleotide that is subject to methylation-mediated repression. Mtb infection reduced CpG methylation across this region to upregulate DUSP14, leading to suppressed JNK phosphorylation via its phosphatase activity, reduced pro-inflammatory cytokine production, and promoted intracellular bacterial survival. Knockdown of DUSP14 decreases bacterial burden and increases cytokine secretion. These findings reveal a functional link between genetic variation and immune response in TB and point to DUSP14 as a potential target for host directed therapy, although further validation in primary cells or using virulent strains and in vivo models is needed. Full article

Gastric cancer is among the leading causes of cancer-related deaths worldwide. Modern treatment approaches include nanoparticles (NPs) designed to target cancer cells, which release a therapeutic cargo facilitating the inhibition of their expansion, thereby improving anti-tumor therapies. The success of NPs, created to deliver anticancer agents and biologically active compounds, may depend on selecting the way to target cancer cells. This study focused on examining the effects of NPs made of polylactic acid (PLA) with histamine (His) end groups and loaded with 5-fluorouracil (5-FU), a known anticancer drug (PLA-His-5-FU), on human gastric cancer AGS cells in vitro. The incubation of AGS cells with PLA-His-FU NPs resulted in diminished mitochondrial membrane potential and the induction of cell apoptosis, along with cell cycle arrest and the reduction of cell proliferation. Furthermore, the NPs tested provoked the secretion of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β by AGS cells and induced the activation of the nuclear factor kappa B (NF-κB) signaling pathway in THP-1 blue monocytes, which indicates the ability to promote the development of a milieu for the infiltration and activation of immunocompetent cells. NPs did not increase intracellular adhesion molecule (ICAM-1) deposition on AGS cells, thus potentially preventing the distribution of cancer cells. In conclusion, PLA-His-5-FU NPs show promising anticancer activity for gastric cancer AGS cells in vitro, better than PLA-OH-5-FU, and can be used in further in vivo studies to confirm this activity. Full article

Rosacea is a chronic inflammatory skin disorder driven by dysregulated cathelicidin processing and excessive LL-37, which triggers a circuit involving Toll-like receptor 2 (TLR2)/kallikrein-5 (KLK5)-dependent amplification and downstream mechanistic target of rapamycin complex 1 (mTORC1), NF-κB, and NLR family pyrin domain containing 3 (NLRP3) inflammasome pathways. We hypothesized that poly-D,L-lactic acid (PDLLA) could attenuate this inflammatory cascade by inducing macrophage-derived interleukin (IL)-10. PDLLA increased IL-10 secretion from THP-1-derived macrophages in a dose-dependent manner. In LL-37-stimulated HaCaT keratinocytes, LL-37 decreased phosphorylated signal transducer and activator of transcription (pSTAT3)/STAT3, DNA damage-inducible transcript 4 (DDIT4), and phosphorylated AMP-activated protein kinase (pAMPK)/AMPK while increasing phosphorylated protein kinase B (pAKT)/AKT and mTORC1 activation; conditioned media from PDLLA-treated macrophages (CM_PDLLA) restored pSTAT3/STAT3, DDIT4, and pAMPK/AMPK, reduced pAKT/AKT, and suppressed pmTOR/mTOR. CM_PDLLA attenuated downstream inflammatory responses, including NF-κB nuclear translocation, VEGF production, and NLRP3-inflammasome-mediated IL-18 secretion. These findings were validated using an intradermal LL-37-injected mouse model. Compared with the normal control/saline group, LL-37/saline decreased IL-10, pSTAT3/STAT3, DDIT4, and pAMPK/AMPK while increasing pAKT/AKT, pmTOR/mTOR, pS6K/S6K, TLR2/KLK5/LL-37, NF-κB, VEGF, and NLRP3 inflammasome/IL-18 signaling; PDLLA partially restored the STAT3/DDIT4–AMPK regulatory pattern and suppressed these disease-associated signals. Consequently, PDLLA treatment led to a pronounced reduction in clinical lesion area. Overall, PDLLA may attenuate LL-37-driven cutaneous inflammation by promoting an IL-10-linked STAT3/DDIT4–AKT/AMPK program that suppresses mTORC1 and disrupts cathelicidin amplification, supporting its potential as an injectable immunomodulatory approach for rosacea-like skin inflammation. Full article

Mycobacterium avium (M. avium) is an opportunistic intracellular pathogen causing chronic pulmonary disease in immunocompromised individuals, particularly in those with HIV/AIDS. Current treatments present challenges due to duration, antibiotic resistance and toxicity, creating a need for novel treatments. Glutathione (GSH), a key intracellular antioxidant, is depleted in immunocompromised individuals. This study evaluated the direct and intracellular antimycobacterial activity of liposomal glutathione (L-GSH) against M. avium. Furthermore, the minimum inhibitory concentration (MIC) and depolarization effects of L-GSH were also determined. Our results indicate that L-GSH has potent direct antimycobacterial activity against M. avium through membrane depolarization and reduces intracellular survival of M. avium in human macrophages. Given the established GSH deficiency in HIV-infected individuals and the clinical need for novel Mycobacterium avium complex (MAC) therapies with favorable safety profiles, these findings support further investigation of L-GSH as a host-directed therapeutic agent for HIV-associated M. avium infections. Full article

Background and Objectives: Neoadjuvant dual HER2 blockade combined with chemotherapy is the standard treatment approach for patients with high-risk early-stage or locally advanced HER2-positive breast cancer. However, the optimal chemotherapy backbone and the predictive value of systemic inflammatory biomarkers remain subjects of ongoing investigation. This study aimed to compare pathologic complete response (pCR) rates between neoadjuvant dose-dense doxorubicin/cyclophosphamide followed by paclitaxel plus trastuzumab and pertuzumab (ddAC+THP) and docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP), and to evaluate the predictive performance of pretreatment inflammatory biomarkers. Materials and Methods: In this multicenter retrospective study, patients with HER2-positive breast cancer treated with neoadjuvant ddAC+THP or TCHP between 2019 and 2025 at three tertiary centers were evaluated. Pretreatment inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and hemoglobin, albumin, lymphocyte, and platelet (HALP) score, were calculated from baseline laboratory parameters. Receiver operating characteristic analyses were performed to determine optimal cutoff values, and logistic regression analyses were used to identify predictors of pCR. Results: A total of 197 patients were included, of whom 138 received ddAC+THP and 59 received TCHP. Overall, 125 patients (63.5%) achieved pCR. The pCR rate was numerically higher in the ddAC+THP group than in the TCHP group (65.2% vs. 59.3%), although the difference was not statistically significant (p = 0.431). Among the evaluated biomarkers, SIRI demonstrated the highest discriminatory performance for predicting pCR (AUC: 0.725, 95% CI: 0.652–0.797), followed by NLR (AUC: 0.673, 95% CI: 0.595–0.750). In multivariable analysis, hormone receptor positivity (OR: 0.291, 95% CI: 0.131–0.645; p = 0.002) and elevated SIRI (>0.845) (OR: 0.088, 95% CI: 0.036–0.216; p < 0.001) were independently associated with lower odds of achieving pCR. No significant difference in pCR was observed between treatment regimens across predefined subgroup analyses. Conclusions: Neoadjuvant ddAC+THP and TCHP achieved comparable pCR outcomes in patients with HER2-positive breast cancer. SIRI was independently associated with a lower likelihood of achieving pCR and showed acceptable discriminatory performance. These findings suggest that SIRI may represent an exploratory, readily available inflammatory biomarker for pCR risk stratification; however, prospective validation is required before clinical application. Full article