Search Results (2,297)

Neuroinflammation driven by microglial activation and α-synuclein (αSyn) aggregation is one of the central features driving Parkinson’s disease (PD) pathogenesis. GM1 ganglioside’s oligosaccharide moiety (OligoGM1) has shown neuroprotective potential in PD neuronal models, but its direct effects on inflammation remain poorly defined. This study investigated the ability of OligoGM1 to modulate microglial activation and αSyn handling in a human in vitro model. Human embryonic microglial (HMC3) cells were exposed to αSyn pre-formed fibrils (PFFs) in the presence or absence of OligoGM1. Microglial activation markers, intracellular αSyn accumulation, and cytokine release were assessed by immunofluorescence and ELISA. OligoGM1 had no effect on microglial morphology or cytokine release under basal conditions. Upon αSyn challenge, cells exhibited increased amounts of ionized calcium-binding adaptor molecule 1 (Iba1), triggered receptor expressed on myeloid cells 2 (TREM2), elevated αSyn accumulation, and secreted pro-inflammatory cytokines. OligoGM1 pre-treatment significantly reduced the number and area of Iba1(+) cells, the intracellular αSyn burden in TREM2(+) microglia, and the release of interleukin 6 (IL-6). OligoGM1 selectively attenuated αSyn-induced microglial activation and enhanced αSyn clearance without compromising basal immune function. These findings confirm and support the potential of OligoGM1 as a multitarget therapeutic candidate for PD that is capable of modulating glial reactivity and neuroinflammatory responses. Full article

Acute Respiratory Distress Syndrome (ARDS) is a complex and devastating form of respiratory failure, with high mortality rates, for which there is no pharmacological treatment. The acute exudative phase of ARDS is characterized by severe damage to the alveolar–capillary barrier, infiltration of protein-rich fluid into the lungs, neutrophil recruitment, and high levels of inflammatory mediators. Rapid resolution of this reversible acute phase, with efficient restoration of alveolar functional integrity, is essential before the establishment of irreversible fibrosis and respiratory failure. Several lines of in vitro and in vivo evidence support the involvement of potassium (K⁺) channels—particularly KvLQT1, expressed in alveolar cells—in key cellular mechanisms for ARDS resolution, by promoting alveolar fluid clearance and epithelial repair processes. The aim of our study was to investigate whether pharmacological activation of KvLQT1 channels could elicit beneficial effects on ARDS parameters in an animal model of acute lung injury. We used the well-established bleomycin model, which mimics (at day 7) the key features of the exudative phase of ARDS. Our data demonstrate that treatments with the KvLQT1 activator R-L3, delivered to the lungs, failed to improve endothelial permeability and lung edema in bleomycin mice. However, KvLQT1 activation significantly reduced neutrophil recruitment and tended to decrease levels of pro-inflammatory cytokines/chemokines in bronchoalveolar lavages after bleomycin administration. Importantly, R-L3 treatment was associated with significantly lower injury scores, higher levels of alveolar type I (HTI-56, AQP5) and II (pro-SPC) cell markers, and improved alveolar epithelial repair capacity in the presence of bleomycin. Together, these results suggest that the KvLQT1 K⁺ channel may be a potential target for the resolution of the acute phase of ARDS. Full article

Macrophage-mediated inflammation is known to be involved in the epithelial–mesenchymal transition (EMT) of various types of cancer. This makes macrophage-derived inflammatory factors prime targets for the development of new treatments. This study uncovers the therapeutic potential and action mechanism of DAB-2-28, a small-molecule derived from para-aminobenzoic acid, in the treatment of breast cancer. The luminal MCF-7 and the triple-negative MDA-MB-231 cancer cell lines used in this study represent, respectively, breast cancers in which the differentiation states are related to the epithelial phenotype of the mammary gland and breast cancers expressing a highly aggressive mesenchymal phenotype. In MCF-7 cells, soluble factors from macrophage-conditioned media (CM-MØ) induce a characteristic morphology of mesenchymal cells with an upregulated expression of Snail1, a mesenchymal marker, as opposed to a decrease in the expression of E-cadherin, an epithelial marker. DAB-2-28 does not affect the differential expression of Snail1 and E-cadherin in response to CM-MØ, but negatively impacts other hallmarks of EMT by decreasing invasion and migration capacities, in addition to MMP9 expression and gelatinase activity, in both MCF-7 and MDA-MB-231 cells. Moreover, DAB-2-28 inhibits the phosphorylation of key pro-EMT transcriptional factors, such as NFκB, STAT3, SMAD2, CREB, and/or AKT proteins, in breast cancer cells exposed to different EMT inducers. Overall, our study provides evidence suggesting that inhibition of EMT initiation or maintenance is a key mechanism by which DAB-2-28 can exert anti-tumoral effects in breast cancer cells. Full article

Background/Objectives: Lysophosphatidylcholine (LPC) is composed of various lipid species, some of which exert pro-inflammatory and others anti-inflammatory activities. However, most of the LPC species analyzed to date are reduced in the serum of patients with inflammatory bowel disease (IBD) compared to healthy controls. To our knowledge, the correlation between serum LPC species levels and measures of inflammation, as well as their potential as markers for monitoring IBD activity, has not yet been investigated. Methods: Thirteen LPC species, varying in acyl chain length and number of double bonds, were measured in the serum of 16 controls and the serum of 57 patients with IBD. Associations with C-reactive protein (CRP) and fecal calprotectin levels as markers of IBD severity were assessed. Results: Serum levels of LPC species did not differ between the healthy controls and the entire patient cohort. In patients with IBD, serum levels of LPC 16:1, 18:0, 18:3, 20:3, and 20:5, as well as total LPC concentrations, showed inverse correlations with both CRP and fecal calprotectin levels, indicating an association with inflammatory activity. Nine LPC species were significantly reduced in patients with high fecal calprotectin compared to those with low values. LPC species with 22 carbon atoms and 4 to 6 double bonds were not related to disease activity. Stool consistency and gastrointestinal symptoms did not influence serum LPC profiles. Corticosteroid treatment was associated with lower serum LPC 20:3 and 22:5 levels, while mesalazine, anti-TNF, and anti-IL-12/23 therapies had no significant impact on LPC concentrations. There was a strong positive correlation between LPC species containing 15 to 18 carbon atoms and serum cholesterol, triglycerides, and phosphatidylcholine levels. However, there was no correlation with markers of liver disease. Conclusions: Shorter-chain LPC species are reduced in patients with active IBD and reflect underlying hypolipidemia. While these lipid alterations provide insight into IBD-associated metabolic changes, they appear unsuitable as diagnostic or disease monitoring biomarkers. Full article

With the acceleration of the pace of life, increased stress levels, and changes in lifestyle factors such as diet and exercise, the incidence of diseases such as cancer and immunodeficiency has been on the rise, which is closely associated with the impaired antioxidant capacity of the body. Polypeptides and polysaccharides derived from edible fungi demonstrate significant strong antioxidant activity and immunomodulatory effects. Auricularia auricula, the second most cultivated mushroom in China, is not only nutritionally rich but also offers considerable health benefits. In particular, its polysaccharides have been widely recognized for their immunomodulatory activities, while its abundant protein content holds great promise as a raw material for developing immunomodulatory peptides. To meet the demand for high-value utilization of Auricularia auricula resources, this study developed a key technology for the stepwise extraction of polypeptides (AAPP1) and polysaccharides (AAPS3) using a composite enzymatic hydrolysis process. Their antioxidant and immunomodulatory effects were assessed using cyclophosphamide (CTX)-induced immune-suppressed mice. The results showed that both AAPP1 and AAPS3 significantly reversed CTX-induced decreases in thymus and spleen indices (p < 0.05); upregulated serum levels of cytokines (e.g., IL-4, TNF-α) and immunoglobulins (e.g., IgA, IgG); enhanced the activities of hepatic antioxidant enzymes SOD and CAT (p < 0.05); and reduced the content of MDA, a marker of oxidative damage. Intestinal microbiota analysis revealed that these compounds restored CTX-induced reductions in microbial α-diversity, increased the abundance of beneficial bacteria (Paramuribaculum, Prevotella; p < 0.05), decreased the proportion of pro-inflammatory Duncaniella, and reshaped the balance of the Bacteroidota/Firmicutes phyla. This study represents the first instance of synergistic extraction of polypeptides and polysaccharides from Auricularia auricula using a single process. It demonstrates their immune-enhancing effects through multiple mechanisms, including “antioxidation-immune organ repair-intestinal microbiota regulation.” The findings offer a theoretical and technical foundation for the deep processing of Auricularia auricula and the development of functional foods. Full article

Background: Accurate and timely prediction of mortality in intensive care unit (ICU) patients, particularly those with COVID-19, remains clinically challenging due to complex immune responses. Proteomic cytokine profiling holds promise for refining mortality risk assessment. Methods: Serum samples from 89 ICU patients (55 discharged, 34 deceased) were analyzed using a multiplex 21-cytokine panel. Samples were stratified into three groups based on time from collection to outcome: ≤48 h (Group 1: Early), >48 h to ≤7 days (Group 2: Intermediate), and >7 days to ≤14 days (Group 3: Late). Cytokine levels, simple cytokine ratios, and previously unexplored complex ratios between pro- and anti-inflammatory cytokines were evaluated. Machine learning-based feature selection identified the most predictive ratios, with performance evaluated by area under the curve (AUC), sensitivity, and specificity. Results: Complex cytokine ratios demonstrated superior predictive accuracy compared to traditional severity markers (APACHE II, SAPS II, SOFA), individual cytokines, and simple ratios, effectively distinguishing discharged from deceased patients across all groups (AUC: 0.918–1.000; sensitivity: 0.826–1.000; specificity: 0.775–0.900). Conclusions: Multiplex cytokine profiling enhanced by computationally derived complex ratios may offer robust predictive capabilities for ICU mortality risk stratification, serving as a valuable tool for personalized prognosis in critical care. Full article

Obesity remains a major global health challenge with limited therapeutic options. Bromelain, a proteolytic enzyme complex derived from pineapple, has been recognized for its natural anti-inflammatory, anti-edematous, and appetite-suppressing properties. This study aimed to investigate the effects of bromelain on hypothalamic neuropeptides and metabolic markers in a high-fat diet (HFD)-induced obesity model in rats. Thirty-six male Wistar albino rats were randomly divided into four groups: standard diet (SD), standard diet with bromelain (SDBro), high-fat diet (HFD), and high-fat diet with bromelain (HFDBro). Obesity was induced by a 3-month HFD regimen, followed by bromelain supplementation (200 mg/kg/day, orally) for one month. Hypothalamic tissues were analyzed via ELISA for neuropeptide Y (NPY), pro-opiomelanocortin (POMC), glucose transporter 2 (GLUT2), fibroblast growth factor 2 (FGF2), and insulin-like growth factor 1 receptor (IGF1R). While NPY levels showed no significant changes, POMC increased in the HFD and was normalized with bromelain. GLUT2 was downregulated in the HFD and significantly restored by bromelain. FGF2 levels remained unchanged. IGF1R was upregulated in the HFD but reduced by bromelain, with an unexpected increase in SDBro. Overall, bromelain partially reversed HFD-induced disruptions in hypothalamic energy-regulating pathways, particularly affecting GLUT2 and POMC. These findings highlight bromelain’s potential role in central metabolic regulation under dietary stress. Full article

Activation of macrophages plays a key role in both inflammation and oxidative stress, key features of many chronic diseases. Pro-inflammatory M1-like macrophages, in particular, contribute to pro-oxidative environments and are a frequent focus of immunological research. This research examined the effects of kiwifruit allergen Act d 1, in comparison to LPS, on THP-1 macrophages in vitro differentiated under optimized conditions, both in the presence and in the absence of selected vanilloids. THP-1 monocyte differentiation was optimized by varying PMA exposure and resting time. Act d 1 induced M1-like phenotypic changes comparable to LPS, including upregulation of CD80, IL-1β and IL-6 secretion, gene expression of iNOS and NF-κB activation, in addition to increased reactive oxygen species (ROS) and catalase activity. Treatment with specific vanilloids mitigated these responses, primarily through reduced oxidative stress and NF-κB activation. Notably, vanillin (VN) was the most effective, also reducing CD80 expression and IL-1β levels. These results suggest that vanilloids can affect pro-inflammatory signaling and oxidative stress in THP-1 macrophages and highlight their potential to alter inflammatory conditions characterized by similar immune responses. Full article

Disruption of the intestinal epithelial barrier is a key driver of gut-derived inflammation in various disorders, yet strategies to preserve or restore barrier integrity remain limited. To address this, we evaluated a four-strain Bifidobacterium mixture—selected for complementary anti-inflammatory potency and industrial scalability—in lipopolysaccharide (LPS)-challenged RAW 264.7 macrophages and a Caco-2/THP-1 transwell co-culture model. Pretreatment with the probiotic blend reduced nitric oxide (NO) release in a dose-dependent manner by 25.9–48.3% and significantly down-regulated the pro-inflammatory markers in macrophages. In the co-culture system, the formulation decreased these markers, increased transepithelial electrical resistance (TEER) by up to 31% at 10⁵ colony-forming unit (CFU)/mL after 48 h, and preserved the membrane localization of tight junction (TJ) proteins. Adhesion to Caco-2 cells (≈ 6%) matched that of the benchmark probiotic Lacticaseibacillus rhamnosus GG, suggesting direct epithelial engagement. These in vitro findings demonstrate that this probiotic mixture can attenuate LPS-driven inflammation and reinforce epithelial architecture, providing a mechanistic basis for its further evaluation in animal models and clinical studies of intestinal inflammatory disorders. Full article

Volatile organic compounds (VOCs) are highly volatile chemicals in natural and anthropogenic environments, significantly affecting indoor air quality. Major sources of indoor VOCs include emissions from building materials, furnishings, and consumer products. Natural wood products release VOCs, including terpenes and aldehydes, which exert diverse health effects ranging from mild respiratory irritation to severe outcomes, such as formaldehyde-induced carcinogenicity. The temporal dynamics of VOC emissions were investigated, and the toxicological and physiological effects of the VOCs emitted by two types of natural wood, Korean Red Pine (Pinus densiflora) and Japanese Cypress (Chamaecyparis obtusa), were evaluated. Using female C57BL/6 mice as an animal model, the exposure setups included phytoncides, formaldehyde, and intact wood samples over short- and long-term durations. The exposure effects were assessed using oxidative stress markers, antioxidant enzyme activity, hepatic and renal biomarkers, and inflammatory cytokine profiles. Long-term exposure to Korean Red Pine and Japanese Cypress wood VOCs did not induce significant pathological changes. Japanese Cypress exhibited more distinct benefits, including enhanced oxidative stress mitigation, reduced systemic toxicity, and lower pro-inflammatory cytokine levels compared to the negative control group, attributable to its more favorable VOC emission profile. These findings highlight the potential health and environmental benefits of natural wood VOCs and offer valuable insights for optimizing timber use, improving indoor air quality, and informing public health policies. Full article

Background and Objectives: Galectin-3 (Gal-3), a pro-inflammatory cytokine, has been implicated in atherosclerosis and adverse cardiovascular outcomes. While its role in coronary artery disease (CAD) is increasingly recognized, its association with systemic atherosclerosis remains underexplored. Objective: To investigate serum Gal-3 levels in patients with CAD and evaluate correlations between CAD severity and extra-coronary atherosclerotic involvement (carotid, femoral, and radial territories). Materials and Methods: We prospectively enrolled 56 patients with CAD undergoing coronary angiography (42.8% with acute-ACS; 57.2% with chronic coronary syndromes-CCS). Gal-3 levels were measured within 24 h of admission. Atherosclerosis severity was assessed angiographically and through vascular ultrasound of the carotid, femoral, and radial arteries. Patients were stratified by median Gal-3 levels, and clinical follow-up was performed at 1 and 3 months. Results: Gal-3 levels were significantly higher in CAD vs. controls (20.7 vs. 10.1 ng/mL; p < 0.00001) and in ACS vs. CCS (22.18. vs. 17.93 ng/mL; p = 0.019). Gal-3 correlated positively with culprit lesion diameter stenosis (DS) (R = 0.30; p = 0.023) and maximum severity of additional treated lesions (R = 0.62; p = 0.006). Gal-3 also correlated positively with carotid plaque thickness (R = 0.32; p = 0.016), while patients with Gal-3 levels above the median showed increased median values for femoral plaque thickness (32.4 vs. 26.45 mm, p = 0.046). No correlation was found with radial artery calcification. Gal-3 showed moderate discrimination for ACS (AUC = 0.685; cut-off 20.18 ng/mL). On multivariate analysis age, DS, and ACS presentation were independent predictors of Gal-3 above 19.07 ng/mL. Conclusions: Gal-3 levels are elevated in ACS and correlate with atherosclerotic burden, particularly in coronary, carotid, and femoral territories. These findings support Gal-3 as a potential marker of lesion severity and systemic vascular involvement, highlighting its possible role in risk stratification and the monitoring of atherosclerotic disease progression. This study provides integrated insights into the impact of Gal-3 across multiple vascular beds by assessing them concurrently within the same patient cohort. Full article

Natural compounds, particularly flavonoids, have emerged as promising anticancer agents due to their various biological activities and no or negligible toxicity towards healthy tissues. Among these, isorhamnetin, a methylated flavonoid, has gained significant attention for its potential to target multiple cancer hallmarks. This review comprehensively explores the mechanisms by which isorhamnetin exerts its anticancer effects, including cell cycle regulation, apoptosis, suppression of metastasis and angiogenesis, and modulation of oxidative stress and inflammation. Notably, isorhamnetin arrests cancer cell proliferation by regulating cyclins, and CDKs induce apoptosis via caspase activation and mitochondrial dysfunction. It inhibits metastatic progression by downregulating MMPs, VEGF, and epithelial–mesenchymal transition (EMT) markers. Furthermore, its antioxidant and anti-inflammatory properties mitigate reactive oxygen species (ROS) and pro-inflammatory cytokines, restricting cancer progression and modulating tumor microenvironments. Combining isorhamnetin with other treatments was also discussed to overcome multidrug resistance. Importantly, this review integrates the recent literature (2022–2024) and highlights isorhamnetin’s roles in modulating cancer-specific signaling pathways, immune evasion, tumor microenvironment dynamics, and combination therapies. We also discuss nanoformulation-based strategies that significantly enhance isorhamnetin’s delivery and bioavailability. This positions isorhamnetin as a promising adjunct in modern oncology, capable of improving therapeutic outcomes when used alone or in synergy with conventional treatments. The future perspectives and potential research directions were also summarized. By consolidating current knowledge and identifying critical research gaps, this review positions Isorhamnetin as a potent and versatile candidate in modern oncology, offering a pathway toward safer and more effective cancer treatment strategies. Full article

Background: This study presents an innovative approach to cardiovascular disease (CVD) risk prediction based on a comprehensive analysis of clinical, immunological and biochemical markers using mathematical modelling and machine learning methods. Baseline data include indices of humoral and cellular immunity (CD59, CD16, IL-10, CD14, CD19, CD8, CD4, etc.), cytokines and markers of cardiovascular disease, inflammatory markers (TNF, GM-CSF, CRP), growth and angiogenesis factors (VEGF, PGF), proteins involved in apoptosis and cytotoxicity (perforin, CD95), as well as indices of liver function, kidney function, oxidative stress and heart failure (albumin, cystatin C, N-terminal pro B-type natriuretic peptide (NT-proBNP), superoxide dismutase (SOD), C-reactive protein (CRP), cholinesterase (ChE), cholesterol, and glomerular filtration rate (GFR)). Clinical and behavioural risk factors were also considered: arterial hypertension (AH), previous myocardial infarction (PICS), aortocoronary bypass surgery (CABG) and/or stenting, coronary heart disease (CHD), atrial fibrillation (AF), atrioventricular block (AB block), and diabetes mellitus (DM), as well as lifestyle (smoking, alcohol consumption, physical activity level), education, and body mass index (BMI). Methods: The study included 52 patients aged 65 years and older. Based on the clinical, biochemical and immunological data obtained, a model for predicting the risk of premature cardiovascular aging was developed using mathematical modelling and machine learning methods. The aim of the study was to develop a predictive model allowing for the early detection of predisposition to the development of CVDs and their complications. Numerical methods of mathematical modelling, including Runge–Kutta, Adams–Bashforth and backward-directed Euler methods, were used to solve the prediction problem, which made it possible to describe the dynamics of changes in biomarkers and patients’ condition over time with high accuracy. Results: HLA-DR (50%), CD14 (41%) and CD16 (38%) showed the highest association with aging processes. BMI was correlated with placental growth factor (37%). The glomerular filtration rate was positively associated with physical activity (47%), whereas SOD activity was negatively correlated with it (48%), reflecting a decline in antioxidant defence. Conclusions: The obtained results allow for improving the accuracy of cardiovascular risk prediction, and form personalised recommendations for the prevention and correction of its development. Full article

Inflammatory biomarkers, including high-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), and interleukin-6 (IL-6), have been associated with an increased risk of future cardiovascular events. While they provide valuable prognostic information, these associations do not necessarily imply a direct causal role. The combined prognostic utility of these markers, however, remains insufficiently studied. We analysed 3300 well-characterised participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, all of whom underwent coronary angiography. Participants were stratified based on their serum concentrations of hsCRP, SAA, and IL-6. Associations between biomarker combinations and mortality were assessed using multivariate Cox regression and ROC analysis. Individuals with elevated hsCRP and SAA or IL-6 showed higher prevalence rates of coronary artery disease, heart failure, and adverse metabolic traits. These “both high” groups had lower estimated glomerular filtration rate, higher NT-proBNP, and increased HbA1c. Combined elevations of hsCRP and SAA were significantly associated with higher all-cause and cardiovascular mortality in partially adjusted models. However, these associations weakened after adjusting for IL-6. IL-6 alone demonstrated the highest predictive power (AUC: 0.638) and improved risk discrimination when included in multi-marker models. The co-elevation of hsCRP, SAA, and IL-6 identifies a high-risk phenotype characterised by greater cardiometabolic burden and increased mortality. IL-6 may reflect upstream inflammatory activity and could serve as a therapeutic target. Multi-marker inflammatory profiling holds promise for refining cardiovascular risk prediction and advancing personalised prevention strategies. Full article

Current research reported that the number of clinical studies found for botulinum toxin (BoNT) key effects on biochemical biomarkers in head and neck chronic conditions linked to inflammation was very low. There are no systematic reviews of animal studies on this topic, and hence our review aimed to evaluate the quality of the preclinical evidence. We searched PubMed, Scopus, and Web of Science databases, and registries up to 29 January 2024. There were 22 eligible records, and data were available for 11 randomised controlled trials. There were concerns about the risk of bias and great variations of data obtained regarding chronic conditions, which included mostly trigeminal neuralgia. The leading biomarkers were proinflammatory cytokines (IL-1β, TNF-α) and synaptosomal-associated protein-25 (SNAP25), followed by neuron activation marker c-Fos and calcitonin gene-related peptide (CGRP). Overall, data found that BoNT significantly altered the under/over-expression of biomarkers evoked by the investigated disease models and had no effect when the levels of these biomarkers were not changed by the induced chronic conditions in animals. However, there were some mixed results and exceptions, and the certainty evidence found was very low to low. Although the sample sizes detected significant effect size (p < 0.05), most studies are based on male inferior animals, which may limit the recommendations for clinical trials. This study is registered on PROSPERO (CRD42023432411). Full article