Search Results (10,989)

The transcription factor IRF5 maintains macrophages in the pro-inflammatory M1 state. We assessed the effects of siRNA-mediated knockdown of Irf5 on murine bone marrow-derived macrophages (BMDM) in M0, M1 and M2 states. Knockdown of Irf5 in M1 macrophages made them phenotypically similar to M2 macrophages, which was reflected in the decreased expression of the M1 marker iNOS, increased expression of the M2 marker CD206, increased mitochondrial content and respective morphological changes. Interestingly, the M2 phenotype was also affected by the reduction in Irf5. Using atomic force microscopy (AFM), we showed that Irf5 knockdown increases plasma membrane roughness, particularly in M2 macrophages. AFM-based stiffness measurements indicated that Irf5 knockdown altered macrophage elasticity, potentially influencing their functional behavior. Our data suggest a complex role of IRF5 in macrophage polarization, supporting its dual role as a transcriptional activator and repressor both in M1 and M2 states, and highlight the importance of IRF5 in the maintenance of metabolic and functional properties of macrophages. Full article

Mucosal-associated invariant T (MAIT) cells exist in high numbers in the body and have a unique and highly conserved T cell receptor (TCR). They can be activated in a TCR-dependent manner by ligands presented on the monomorphic protein MHC class I-related protein 1 (MR1) which is found on many cell types, including professional antigen presenting cells (APCs) and epithelial cells. This has sparked interest in the potential to exploit the MR1-MAIT cell axis for the development of vaccines against infectious disease. Within this context an MR1 ligand, typically 5-(2-oxopropylideneamino)-d-ribitylaminouracil (5-OP-RU), is administered with or without a Toll-like receptor (TLR) ligand or cytokine in a pan vaccination approach that would prime the immune response to provide protection against a variety of bacterial and viral pathogens. This strategy has led to enhanced protection in murine models of Legionella longbeachae, Francisella tularensis, Klebsiella pneumoniae, Streptococcus pneumoniae and influenza infection. However, studies against Mycobacterium tuberculosis infection have proven less successful. The second vaccination approach involves pairing the MR1 ligand with more conventional antigens that could activate CD4⁺ and/or CD8⁺ T cells. This approach has been successful in murine models of cholera, influenza, and SARS-CoV-2, including in the context of subunit vaccines. However, there are several challenges when using MR1-MAIT cell-mediated vaccine adjuvants. These include the inherent instability of 5-OP-RU and the need for more advanced studies to better understand how the use of MR1 ligands would translate to applications in humans. This review will discuss these aspects and highlight the mechanistic studies that have been undertaken to understand how MAIT cells might elicit their effects within the context of MAIT cell-mediated vaccines for infectious disease. Full article

In November 2023, surface sediments were collected at 46 sites around the main islands of the Zhoushan Archipelago (Dinghai, Daishan, Qushan, and Shengsi) in the East China Sea. The concentrations of Cu, Zn, Cr, Pb, Cd, Hg, and As were determined, together with sediment TOC and Eh. Pollution and ecological risks were evaluated using the single-factor index (Pi), Nemerow pollution index (PN), and Hakanson’s potential ecological risk index (RI). Source apportionment was investigated using FA–PC and EPA PMF 5.0. Mean concentrations (mg/kg) were Zn 77.58, Cr 70.08, Cu 28.44, Pb 18.92, As 9.40, Cd 0.09, and Hg 0.073, with higher levels generally observed near Dinghai, Daishan, and Shengsi. The overall risk was low, whereas Cd and Hg contributed disproportionately to RI. FA–PC suggested two major source groups, and PMF resolved three factors related to (i) agriculture/aquaculture (As), (ii) industrial and domestic effluents (Hg), and (iii) port and ship-related activities (Cd, Cu, Cr, Pb, Zn). The results support targeted management focusing on Cd, Hg, Cu, and As in identified hotspots. Full article

There is increasing evidence that exposure to environmental toxicants may impact fertility, especially during critical windows of reproductive axis development. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons, essential for puberty onset and fertility, originate from the olfactory placode and migrate toward the hypothalamus during development, making them particularly vulnerable to environmental insults. Cadmium (Cd), a widespread heavy metal, is well known for its gonadotoxicity, but its impact on human hypothalamic neuron development remains unclear. Using human fetal GnRH neuroblasts (FNCB4) we investigated the effects of Cd exposure on their morpho-functional and developmental features. Cd induced oxidative stress and COX2 mRNA upregulation, indicative of inflammatory pathway activation, which was accompanied by reduced cell migration and downregulation of motility-related genes. These effects were associated with F-actin disassembly and altered expression of adhesion molecules. Electrophysiological analyses showed that Cd altered membrane potential, increased capacitance and permeability, and disrupted gap junctional communication, as also confirmed by connexin-43 delocalization. Moreover, Cd significantly reduced the expression of specific GnRH neuronal markers, suggesting impaired functional maturation. Overall, our findings provide the first evidence that Cd may interfere with mechanisms crucially involved in human GnRH neuron development, adding new mechanistic insights into the comprehension of how early-life exposure to Cd may contribute to fertility concerns. Full article

Background: Mycoplasma pneumoniae pneumonia (MPP) is a common community-acquired pneumonia in children. Increasing drug resistance highlights the need for more effective treatments with fewer side effects. The Qingfei Tongluo Jiedu formula (QTJD) has demonstrated clinical efficacy against MPP; however, its underlying mechanisms remain unclear. This study aimed to explore the mechanism of QTJD on MPP using network pharmacology and in vitro experiments. Methods: Network pharmacology was used to identify the active compounds and signaling pathways of QTJD in MPP. QTJD-containing serum was prepared, and primary mouse lung and bone marrow cells were isolated to examine the effects of QTJD on macrophage polarization through butyric acid. Cell viability assays, flow cytometry, and quantitative reverse transcription-polymerase chain reaction were performed. GPR109^−/− cells were used to confirm the receptor mediating butyric acid’s action, and Western blotting was employed to assess the MAPK signaling pathway. Results: QTJD promoted macrophage polarization and alleviated the inflammatory response caused by Mycoplasma pneumoniae. High-performance liquid chromatography-electrospray ionization mass spectrometry combined with network pharmacology identified 20 active compounds. Protein-protein interaction analysis revealed 10 core target, including JUN and Tumor Necrosis Factor (TNF), while enrichment analysis highlighted pathways such as Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase-Protein Kinase B. Experimental validation demonstrated that QTJD reduced M1 markers (CD86, CXCL10) by increasing butyrate levels (p < 0.01) and enhanced M2 markers (CD206, Arg-1, MRC-1), promoting M2 polarization. QTJD inhibited ERK1/2, p38, and JNK1/2 (p < 0.01). In GPR109A^−/− mice macrophages, QTJD suppressed p38 and JNK1/2 (p < 0.01) but showed no effect on ERK1/2 (p > 0.05), confirming involvement of the butyrate-GPR109A-MAPK pathway. Conclusions: QTJD effectively alleviates MPP by regulating macrophage polarization through the butyrate-GPR109A-MAPK pathway. Future studies should explore how QTJD modulates pulmonary immunity through gut microbiota and butyrate production and elucidate its immunoregulatory mechanisms along the gut-lung axis using multi-omics approaches. Full article

Groundwater, a critical resource for regional water security and public health, faces escalating threats from heavy metal contamination—a pressing environmental challenge worldwide. This study focuses on the central-south Hunan region of China, a mineral-rich, densely populated area characterized predominantly by non-point-source pollution, aiming to systematically unravel the spatial patterns, source contributions, and associated health risks of heavy metals in local groundwater. Based on 717 spring and well water samples collected in 2024, we determined pH and seven heavy metals (As, Cd, Pb, Zn, Fe, Mn, and Tl). By integrating hydrogeological zoning, lithology, topography, and river networks, the study area was divided into 11 assessment units, clearly revealing the spatial heterogeneity of heavy metals. The results demonstrate that exceedances of Cd, Pb, and Zn were sporadic and point-source-influenced, whereas As, Fe, Mn, and Tl showed regional exceedance patterns (e.g., Mn exceeded the standard in 9.76% of samples), identifying them as priority control elements. The spatial distribution of heavy metals was governed the synergistic effects of lithology, water–rock interactions, and hydrological structure, showing a distinct “acidic in the northeast, alkaline in the southwest” pH gradient. Combined application of the APCS-MLR and PMF models resolved five principal pollution sources: an acid-reducing-environment-driven release source (contributing 76.1% of Fe and 58.3% of Pb); a geogenic–anthropogenic composite source (contributing 81.0% of Tl and 62.4% of Cd); a human-perturbation-triggered natural Mn release source (contributing 94.8% of Mn); an agricultural-activity-related input source (contributing 60.1% of Zn); and a primary geological source (contributing 89.9% of As). Monte Carlo simulation-based health risk assessment indicated that the average hazard index (HI) and total carcinogenic risk (TCR) for all heavy metals were below acceptable thresholds, suggesting generally manageable risk. However, As was the dominant contributor to both non-carcinogenic and carcinogenic risks, with its carcinogenic risk exceeding the threshold in up to 3.84% of the simulated adult exposures under extreme scenarios. Sensitivity analysis identified exposure duration (ED) as the most influential parameter governing risk outcomes. In conclusion, we recommend implementing spatially differentiated management strategies: prioritizing As control in red-bed and granite–metamorphic zones; enhancing Tl monitoring in the northern and northeastern granite-rich areas, particularly downstream of the Mishui River; and regulating land use in brick-factory-dense riparian zones to mitigate disturbance-induced Mn release—for instance, through the enforcement of setback requirements and targeted groundwater monitoring programs. This study provides a scientific foundation for the sustainable management and safety assurance of groundwater resources in regions with similar geological and anthropogenic settings. Full article

Background: Coronavirus disease 2019 (COVID-19) vaccines deliver mRNA packaged in lipid nanoparticles via intramuscular injection. This study investigated several factors influencing antibody production patterns and adverse reactions after vaccination with COVID-19 vaccines. Methods: Among the participants of the Iwaki Health Promotion Project (IHPP), 211 individuals who consented to this study were surveyed regarding antibody titers and adverse reaction symptoms following vaccination. A machine learning approaches such as ridge regression, elastic-net, light gradient boosting, and neural network were applied to extract the variables, and Bayesian network analysis was applied to explore causal relationships between health data and the multi-omics dataset obtained from the IHPP health checkups. Results: Females with lower levels of free testosterone experienced more adverse reactions than males. Moreover, the immune system is more active in younger individuals, causing adverse reactions and higher antibody production. The Spikevax vaccine induced adverse reaction symptoms with higher antibody production in cases of fever. Meanwhile, drinking 2–3 cups of green tea daily seemed to be effective in increasing antibody production. Factors increasing side effect risk include blood natural killer cell count and muscle quality in the vaccinated arm. Plasma metabolome metabolite concentrations, tongue coating bacterial colonization, and folate intake were also identified as factors influencing side effect risk. Furthermore, characteristics of participants at risk for fever symptoms included longer telomere length, higher antibody production patterns, and higher CD4-positive T cell counts. Conclusions: Further investigation of these identified influencing factors is expected to clarify the rationale for new vaccine development and identify lifestyle and dietary habits that enhance vaccine efficacy. Full article

Heavy metal contamination poses critical challenges for the cultivation of medicinal plants. This study explores cadmium (Cd)-induced morpho-physiological and metabolic responses in Salvia officinalis (So) and the rare endemic Salvia ceratophylloides (Sc). Plants were exposed to cadmium contamination corresponding to 5 and 10 mg kg⁻¹ Cd (100% and 200% of the Italian regulatory limit) and assessed through gas exchange, leaf anatomy, mineral profiling, polyphenol composition, antioxidant activity, and a preliminary ecotoxicological evaluation using the Artemia salina lethality bioassay. Cd predominantly accumulated in roots, reflecting a partial exclusion strategy, and caused alterations in leaf traits, water relations, and nutrient balance. While total polyphenols generally declined, species-specific responses emerged: S. ceratophylloides increased caffeic acid derivatives, whereas S. officinalis accumulated caffeic acid, lithospermic acid A, quercetin 3-O-glucuronide, and apigenin-O-pentoside at the highest Cd exposure. Polyphenol shifts were strongly associated with antioxidant capacity. Despite higher growth sensitivity, S. ceratophylloides extracts exhibited no toxicity in the A. salina assay, indicating effective metal sequestration and low bioavailability, whereas S. officinalis extracts induced moderate to high toxicity. These findings reveal contrasting Cd tolerance and detoxification strategies, highlighting the potential of integrating plant stress physiology with ecotoxicological assessment and phytostabilization approaches to safely cultivate medicinal species on contaminated soils. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease and is characterized by excessive lipid accumulation in hepatocytes. Endoplasmic reticulum (ER) stress and inflammation play important roles in hepatic lipid accumulation. Although CILP2 has been implicated in lipid metabolism, its role in MASLD remains unclear. Hepatic steatosis was induced in mice by a high-fat diet in this study. CILP2 was overexpressed in mouse livers and in vitro hepatocytes using the Ad-CILP2 adenovirus. CILP2 KO mice were also used in the experiments. Liver tissues and hepatocytes were collected for further analysis. CILP2 expression was upregulated in steatotic liver tissue and hepatocytes. CILP2 overexpression upregulated genes related to fatty acid synthesis (Srebp-1c, Fasn, Acc, Scd1, and Cd36), promoted lipid accumulation, and elevated the expression of proinflammatory cytokines (Il6, Tnf, and Il1b). Conversely, CILP2 knockout reduced high-fat diet-induced hepatic steatosis and improved glucose metabolism. Mechanistically, CILP2 activated the IRE1α/XBP1 branch of the ER stress pathway, thereby promoting lipid synthesis and inflammation, effects that were partially alleviated by 4-PBA and STF-083010 treatments. Our findings indicate that CILP2 contributes to hepatic lipid accumulation and inflammation via the IRE1α/XBP1 pathway and may represent a potential therapeutic target for MASLD intervention. Full article

Diet plays a central role in shaping the composition and metabolic activity of the oral microbiota, thereby influencing both oral and systemic health. Disturbances in this delicate host–microbe balance, triggered by dietary factors, smoking, poor oral hygiene, or antibiotic use, can lead to microbial dysbiosis and increase the risk of oral diseases such as periodontitis, as well as chronic systemic disorders including diabetes, cardiovascular disease, Alzheimer’s disease, and certain cancers. Among dietary contaminants, exposure to toxic heavy metals such as cadmium (Cd), lead (Pb), mercury (Hg), nickel (Ni), and arsenic (As) represents an underrecognized modifier of the oral microbial ecosystem. Even at low concentrations, these elements can disrupt microbial diversity, promote inflammation, and impair metabolic homeostasis. Saliva has recently emerged as a promising, non-invasive biofluid for monitoring nutritional status and early metabolic alterations induced by diet and environmental exposures. Salivary biomarkers, including metabolites, trace elements, and microbial signatures, offer potential for assessing the combined effects of diet, microbiota, and toxicant exposure. This review synthesizes current evidence on how diet influences the oral microbiota and modulates susceptibility to heavy metal toxicity. It also examines the potential of salivary biomarkers as integrative indicators of nutritional status and metabolic health, highlights methodological challenges limiting their validation, and outlines future research directions for developing saliva-based tools in personalized nutrition and precision health. Full article

Chronic lymphocytic leukemia (CLL) is a dynamic malignancy in which intraclonal subfractions differ in activation history and responsiveness to microenvironmental signals. Here, we investigated the expression and inducibility of IL-12 family receptor subunits (IL-23R, IL-12Rβ1, IL-12Rβ2) and the related receptor complexes in recirculating CLL cells, with a focus on CXCR4/CD5-defined fractions: the proliferative fraction (PF; CXCR4^dim/CD5^bright; most recently divided, tissue-emigrated cells) and the resting fraction (RF; CXCR4^bright/CD5^dim; older, quiescent cells). At baseline, IL-12Rβ1 was enriched in the PF and was associated with a higher proportion of cells expressing IL-23R and IL-12R receptor complexes. Concomitantly, RT-qPCR disclosed higher IL-12Rβ1 mRNA levels. Following antigen-independent activation with CpG or CpG + IL-15, there was a marked increase in IL-23R and IL-12Rβ1 but not in IL-12Rβ2 surface expression, resulting in preferential upregulation of the IL-23R complex over the IL-12R complex. Fraction-specific analyses showed stronger induction of IL-23R and IL-23R complex expression in PF compared with RF. These findings identify an intraclonal bias toward IL-23 responsiveness in the CLL cells with a phenotype of recently divided, tissue-emigrated cells and suggest the IL-23/IL-23R axis as a potential therapeutic target. Full article

Microplastics (MPs) can serve as bearers of microorganisms and additional contaminants. However, the functional composition and assembly processes of plastisphere bacteria in co-contaminated soil–plant systems are not yet well understood. Using a pot experiment, we examined the effects of both individual and combined cadmium (Cd) and polypropylene (PP) MP contamination on the development of the bioenergy plant sorghum. The bacterial community, co-occurrence networks, and assembly processes in the rhizosphere soil and PP plastisphere were investigated using high-throughput sequencing. Compared with contamination by a single compound, combined contamination with Cd and PP had a more potent inhibitory effect on the development of sorghum. PCoA and diversity indices indicate that the bacterial community on PP plastics is structurally simpler than that in rhizosphere soil. The PP plastisphere could recruit bacteria from the genera Sphingomonas, Rhizobium, and Bacillus. The bacterial communities in the soil and the PP plastisphere were mostly formed by stochastic processes, with diffusion limitation playing a greater role in the bacterial community in the PP plastisphere. Co-occurrence network analysis revealed differences between the bacterial communities in the soil and in the PP plastisphere, with the network in the PP plastisphere showing lower complexity and connectivity. Functional prediction revealed that the prevalence of nitrogen cycling genes was greater in the PP plastisphere than in the dirt and that the PP plastisphere presented greater metabolic activity. The relative prevalence of metabolic pathways associated with human diseases was markedly elevated in the PP plastisphere, which may be correlated with the dissemination of pathogenic microorganisms. These findings indicate that the PP plastisphere, as a distinct microbial niche, might attract certain bacteria, consequently affecting the functional characteristics of cocontaminated soil–plant systems. Full article

Hepatitis C virus (HCV) still lacks a licensed vaccine. The envelope glycoprotein E2 is a key neutralizing target, but its dense N-glycan shield can hinder epitope exposure. In this study, we revisit E2 glycan editing and examine whether single-site deletion preserves antigen integrity while improving immune responses in mice under a DNA immunization setting. Using a secreted E2 ectodomain (sE2384–661), we generated five N to D mutants at conserved sites (N1, N2, N4, N6, and N11) and evaluated them in a unified DNA immunization model with identical CpG content and delivery conditions across groups. The N2 mutant (N423, sE2-N2) maintained expression, secretion, and ER localization; furthermore, in mice, it was associated with higher anti-E2 titers and greater inhibition of H77 (genotype 1a) HCVcc at the tested dilutions, with limited activity against Con1 (1b). Cellular analyses showed increased IFN-γ ELISPOT counts and higher frequencies of granzyme B⁺/perforin⁺ CD8⁺ T cells after N2 immunization, while IL-4 remained low. Functionally, N2 elicited stronger specific lysis of CT26-sE2 targets in vitro and slowed CT26-sE2 tumor growth in vivo. In HCV-infected ICR^4R+ mice, therapeutic vaccination with sE2-N2 reduced blood HCV RNA and hepatic readouts compared with sE2. A monoclonal antibody isolated from sE2-N2-immunized mice (1C1) neutralized HCVcc in vitro and, after passive transfer, lowered viremia and liver signals in infected mice. Collectively, these findings indicate that selective removal of the N2 glycan preserves antigen properties and is associated with improved humoral and cellular immunity and measurable in vivo activity, supporting targeted glycan editing as a practical strategy to refine E2-based HCV vaccines. Full article

Background/Objectives: Differential diagnosis between Crohn’s disease (CD) and ulcerative colitis (UC) can be sometimes difficult resulting in the diagnosis of unspecified inflammatory bowel diseases (IBD-U). Data suggest that IgG antibodies against integrin αvβ6 (V6 Ab) help to identify UC patients. Recent studies suggest that measuring V6 Ab serum levels may be valuable for differential diagnostic purposes. The primary objective of the study was to assess the sensitivity and specificity of V6 Ab serum-level measurement in our IBD population to differentiate between colonic/ileocolonic CD and UC with an established diagnosis. Furthermore, we assessed the correlation between disease characteristics, activity and V6 Ab serum levels in UC patients. Methods: Consecutive IBD patients with an established diagnosis undergoing control colonoscopy in a tertiary IBD center were included. Baseline demographic data, current treatment, disease extent, clinical, biomarker, endoscopic and histologic disease activity were collected. V6 Ab serum levels were measured with the Anti-Integrin αvβ6 ELISA Kit (RUO). Patients’ written informed consent was obtained. Results: A total of 40 IBD patients, including 10 CD and 30 UC patients (15 with clinical activity and 15 in clinical remission) were enrolled. V6 Ab serum levels were significantly higher in UC patients compared to CD (p = 0.039). ROC analysis found 1.33 U/mL to be the best cut-off level (p = 0.04; AUC: 0.71) with 100% sensitivity and 50% specificity and a positive predictive value of 85.7% and a negative predictive value of 100% to differentiate between UC and CD. No significant correlation was found between V6 Ab serum levels and CRP (p = 0.057), fecal calprotectin (p = 0.77), endoscopic activity (p = 0.624) or disease extent (p = 0.624) in UC patients. Conclusions: Our study supports the value of V6 Ab serum level measurement as a differential diagnostic tool in IBD patients; however, the optimal cut-off value is yet to be determined. Our data do not support its role in disease activity monitoring. Full article

Optimizing efficient electrode materials that combine high energy density, rapid charge transport, and excellent cycling stability remains a challenge for advanced supercapacitors. Here, we report the synthesis of an innovative copper(I)-based metal–organic framework (MOF), Cu₃(NDI)₃, prepared via a simple solvothermal method using N,N’-bis(3,5-dimethylpyrazol-4-yl)-naphthalene diimide (H₂NDI-H) as a linker. Structural analyses (XRD, FTIR, SEM, EDX, and BET) confirmed the formation of a highly crystalline, porous MOF. Integration of this MOF into laser-induced graphene (LIG) matrices yielded hybrid electrodes with enhanced structural characteristics and electrochemical activity, compared to its only-LIG counterpart. Electrochemical studies (CV, CD, EIS) revealed that the LIG–MOF electrode exhibited the highest performance, delivering a specific capacitance of 4.6 mF cm⁻² at 0.05 mA cm⁻², and an areal energy density of 60.03 μWh cm⁻² at a power density of 1292.17 μW cm⁻², outperforming both LIG and MOF–LIG configurations. This enhancement arises from the synergetic interaction between the conductive LIG network and the redox-active Cu₃(NDI)₃ framework, highlighting the potential of LIG–MOF hybrids as next-generation materials for high-performance supercapacitors. Full article