Search Results (874)

Streptococcus suis (S. suis) is an important zoonotic pathogen that causes severe disease in both humans and pigs, leading to substantial economic losses in the swine industry. Extracellular vesicles (EVs), as critical mediators of host–pathogen interactions, play key roles in bacterial virulence and disease progression. This study aimed to investigate the biological properties of S. suis EVs and elucidate their role in the bacterium’s pathogenesis. We isolated and characterized S. suis EVs, which were found to contain diverse protein molecules. EVs were efficiently internalized by mammalian cells, and concentrations below 50 μg/mL did not affect cell viability. Following uptake, EVs suppressed the production of key pro-inflammatory cytokines (TNF-α, IL-1β, and IL-8) by modulating macrophage metabolism. They also downregulated the expression of major histocompatibility complex class II (MHC-II) and adhesion molecules (VCAM-1 and ICAM-1) during subsequent infections, potentially impairing macrophage-mediated clearance. In addition, EVs served as vectors for efficient cargo delivery and facilitated S. suis adhesion to and invasion of endothelial cells. In infection models, EVs markedly enhanced lethality in Galleria mellonella larvae and promoted tissue colonization in murine models. These findings suggest that S. suis EVs are key mediators of host–pathogen interactions, contributing to colonization and disease pathogenesis. Moreover, they offer novel insights and potential strategies for the prevention and control of S. suis infections. Full article

Long COVID (LC) is characterized by a wide range of symptoms, the causes of which remain unclear. We investigated associations between inflammatory and coagulation factors, adaptive immune response to SARS-CoV-2, and LC. We enrolled 196 unvaccinated individuals with SARS-CoV-2 (March–June 2020). Blood samples were collected at three (T3M) and twelve (T12M) months post infection. Plasma concentrations of coagulation factors (D-Dimer, E-Selectin, ICAM-1, VCAM-1) and inflammatory markers (IL-6, IL-8, TNF-α, IL-1β) were measured by ELISA, and SARS-CoV-2-specific T-cell response was assessed by Elispot. LC occurred in 66/196 patients (34%); 77.8% had been hospitalized. Respiratory symptoms were present in 54%, fatigue in 30%, and neuropsychological symptoms in 14%. At T3M, hospitalized patients exhibited higher levels of ICAM-1, VCAM-1, and IL-6, along with increased immunoreactivity. LC patients exhibited elevated IL-8 and TNF-α and enhanced immunoreactivity at T3M, though these differences were not observed at T12M. Inflammatory and coagulation markers were altered at three months after acute infection, with some changes persisting at one year, suggesting a long-term immunological impact of SARS-CoV-2 on the inflammatory response. A SARS-CoV-2-specific T-cell response was still detectable at T12M, albeit at a lower level than at T3M, suggesting the persistence of protective memory T-cells beyond the acute phase. Full article

Background/Objectives: The tumour microenvironment in pancreatic ductal adenocarcinoma (PDA) is highly complex, influencing both vascular function and therapy response. P21-activated kinases (PAKs) are key regulators of the cellular and immune system, but the specific roles of PAK1 and PAK4 in pancreatic tumour vasculature and chemotherapy sensitivity are unclear. This study investigated the effects of PAK1 and PAK4 on tumour vasculature and therapeutic response in an immunocompromised mouse model. Methods: KPC-derived wild type (WT), PAK1 knockout (KO), PAK4KO, or PAK1&4KO pancreatic cancer cells were injected subcutaneously into SCID mice, followed by gemcitabine treatment. Tumour growth, vessel density, pericyte coverage, and endothelial adhesion molecule expression were analysed by histology and immunostaining. A proteomic study was used to identify protein changes. Results: PAK1KO significantly reduced tumour growth, enhanced vascular normalisation, upregulated stromal ICAM-1 and VCAM-1, but reduced gemcitabine efficacy. PAK4KO did not inhibit tumour growth but increased vessel diameter and enhanced gemcitabine efficacy. Proteomics study indicated that PAK1KO downregulated proteins involved in the VEGF pathway, while PAK4KO upregulated most proteins involved in the VEGF pathway and downregulated DNA repair proteins, contributing to improved chemotherapy sensitivity. The double knockout of PAK1 and PAK4 did not inhibit tumour growth, although it stimulated vascular normalisation, indicating an outcome balanced between PAK1 and PAK4. Conclusions: PAK1 and PAK4 differentially regulated pancreatic tumour vasculature and chemotherapy response. PAK1KO suppressed tumour growth by reducing angiogenesis and enhancing vascular normalisation, whereas PAK4KO enhanced gemcitabine efficacy through vessel dilation. Full article

Human rhinovirus 16 (HRV-16) is a major cause of common colds and can exacerbate asthma and COPD, yet no approved antiviral treatments exist. Heparin, a highly sulfated polysaccharide, is known to block viral infection of many viruses that require attachment to heparan sulfate proteoglycans (HSPGs). Here, we investigated whether heparin inhibits HRV-16 infection. HRV-16 uses ICAM-1 as its attachment receptor and lacks a confirmed HSPG-binding mechanism. Notably, heparin inhibited HRV-16 infection in vitro in a dose- and time-dependent manner. Pre-treatment of either cells or virus particles with unfractionated heparin significantly reduced HRV-16 RNA expression at 24 and 48 h post-infection. In contrast, low-molecular-weight heparins blocked infection of HRV-16 significantly less effectively compared to unfractionated heparins. Our findings suggest that the inhibitory effect of unfractionated heparin on HRV-16 infection is likely independent of specific HSPGs interactions and may be mediated by the size and highly negative charge of unfractionated heparin. Importantly, the ability of unfractionated heparin to block viruses that do not require HSPGs for attachment implies a broader antiviral potential as a prophylactic or therapeutic agent against a variety of respiratory viruses. Full article

Cholangiocarcinoma (CCA), an aggressive biliary tract cancer whose prevalence is rising, particularly in Thailand, is marked by elevated oxidative stress driven by chronic inflammation, parasitic infections, and dysregulated redox signaling. This study investigates the anticancer potential of tiliacorinine using a silico approach, including drug-likeness, ADMET, network pharmacology, molecular docking, and dynamics simulations. Tiliacorinine and 216 predicted targets were identified, with 79 overlapping CCA-related genes from GeneCards. GO and KEGG analyses revealed involvement in cell migration, membrane structure, kinase activity, and cancer-associated pathways. Network and PPI analyses identified ten key targets, including SRC, HIF1A, HSP90AA1, NFKB1, MTOR, MMP9, MMP2, PIK3CA, ICAM1, and MAPK1. Tiliacorinine showed the strongest affinity for MTOR (−10.78 kcal/mol, K_i = 12.62 nM), binding at the same site as known inhibitors with superior energy and specificity, supported by hydrogen bonding at ASP950 and hydrophobic interactions. Tiliacorinine also demonstrated strong binding to SRC, MMP9, and MAPK1. Molecular dynamics simulations revealed stable binding of tiliacorinine to MTOR, particularly at residues ASP950, TRP1086, and PHE1087. Comparative analysis with the MTOR–GDC-0980 complex confirmed consistent interaction patterns, reinforcing the structural stability and specificity of tiliacorinine. These results highlight its strong pharmacological potential and support its candidacy as a promising lead compound for cholangiocarcinoma therapy. Full article

Calafate berry, an ancient perennial shrub of South America (Chile and Argentina), produces a high antioxidant capacity berry with a high polyphenol (1344.2–6553 mg GAE/100 g d.w.) and anthocyanin (26.5–80 mg C-3-G/100 g d.w.) content. The beneficial effects of calafate berries on human health are related to the anti-inflammatory, hypoglycemic, anticancer, and antioxidant properties that the berries possess, which have been confirmed through evidence to date, primarily from in vitro, ex vivo, and animal studies. Several investigations have shown a relationship between the consumption of calafate and a reduction in the risk of contracting cardiovascular diseases (CVD). This was evident in changes in plasma level biomarkers related to CVD, such as thrombomodulin (−24%), adiponectin (+68%), sE-selectin (−34%), sICAM-1 (−24%) and proMMP-9 (−31%), and changes in the production of OH radicals in plasma (−17%) after calafate intake. Calafate may have an antithrombotic role that supports cardiovascular health by lowering the Atherogenic and Cardiovascular Risk Indices. Various authors indicate delphinidin-3-glucoside (384–386 mg/100 g) as the primary bioactive compound responsible for the beneficial properties of Calafate. Although some studies report calafate’s health benefits, scientific evidence, especially in humans, remains limited. Meanwhile, Chile is working to domesticate and cultivate calafate, aiming to turn it from a wild native berry into a sustainable crop for use in the antioxidants and nutraceuticals industry. The lack of human clinical trials emphasizes the need for future research to validate calafate’s health benefits berry. Full article

Myocarditis is an inflammatory disease of the heart characterized by a complex interplay between innate and adaptive immune responses. The innate immune system provides first-line defense and includes soluble molecules, including macrophages, neutrophils, dendritic cells, and molecular mediators, but lacks immunological memory. In contrast, the adaptive immune system, via T and B lymphocytes, offers high specificity and long-term memory, which can sometimes target myocardial tissue, causing autoimmune injury. Particularly, acute myocarditis is characterized by dysregulated immune signaling, with cytokines (IL-2, IFN-γ, IL-12, IL-4, IL-10) and chemokines (MCP-1, CXCL4, CXCL10) driving disease progression, while adhesion molecules (ICAM-1, VCAM-1, VAP-1) promote leukocyte trafficking and cardiac inflammation. The balance between pro-inflammatory and regulatory responses determines disease outcomes, ranging from resolution with recovery to fulminant myocarditis or progression to dilated cardiomyopathy. Emerging therapeutic approaches targeting cytokines, chemokines, and adhesion molecules, along with established immunosuppressive treatments, underline the potential for modulating immune responses in myocarditis and, thereby, improving patient outcomes. Full article

Prediabetes increases oxidative stress and the risk of type 2 diabetes and related cardiovascular diseases. Previous trials have shown antioxidant-rich strawberries improve this risk, but effects on antioxidant markers are inconclusive. This 28-week randomized controlled crossover trial evaluated the effects of freeze-dried strawberries (FDS) on fasting glucose, serum antioxidant status, and vascular inflammation in adults with prediabetes not on glucose-lowering medications. Participants were assigned to FDS (32 g/day ~ 2.5 servings of whole strawberries) or control (usual diet, no strawberries) for 12 weeks each, separated by a 4-week washout (n = 25/treatment period). Biomarkers were measured at baseline, 12, 16 (baseline 2), and 28 weeks. A mixed-model analysis of variance detected differences between groups, adjusting for covariates. Compared to control, FDS significantly improved serum superoxide dismutase (0.08 ± 0.04 U/mL), glutathione [(GSH): 1.8 ± 0.96 µmol/L], antioxidant capacity [(AC): 5.9 ± 3.2 µmol/L], β-carotene (113.9 ± 15.8 nmol/L), fasting glucose (97 ± 12 mg/dL), intercellular adhesion molecule [(ICAM): 56.0 ± 21.8 ng/mL], and vascular cell adhesion molecule [(VCAM): 440 ± 163 ng/mL] (all p < 0.05). ICAM was inversely correlated with GSH (r = −0.21), AC (r = −0.15), and β-carotene (r = −0.13) (all p < 0.05). VCAM was inversely correlated with AC (r = −0.12) (p < 0.05). Catalase, glutathione reductase, glutathione peroxidase, α-carotene, P-selectin, and E-selectin were unaffected. Our findings support strawberry intake as a dietary intervention for improving blood glucose control and antioxidant status in adults with prediabetes. Full article

In the current study, we focus on analyzing the relationship between changes in micro- and macrocirculation and different stages of metabolic memory. We hypothesized that early poor glycemic control induces lasting endothelial changes detectable in pediatric type 1 diabetes (T1D) microcirculation. We assessed microcirculation structure and function using capillaroscopy, transcutaneous oxygen pressure (TcPO₂), and optical coherence tomography (OCT). We evaluated macrovascular circulation using pulsatility index (PI), ankle-brachial index (ABI) and pulse pressure (PP). We also examined the relationship between circulation parameters, the age at onset, and diabetes duration. The study included 67 patients with uncomplicated type 1. We divided all patients into four groups based on their HbA_1c levels at T1D onset and their average HbA_1c after one and two years. We assessed the concentrations of TNF-α, IL-35, IL-4, IL-10, IL-18, IL-12, serum angiogenin, VEGF, sVCAM-1, ICAM-1, sP-Selectin, AGEs, and sRAGE. We compared subgroups with different levels of metabolic memory but comparable T1D duration and age at diagnosis. Micro- and macrovascular parameters were similar between the groups. Our comparison of subgroups with identical metabolic memory but different durations and ages at diagnosis revealed clear differences. The subgroup with a shorter T1D duration showed higher capillary density and a smaller inter-capillary distance compared to those with a longer diabetes duration. This subgroup with shorter duration had significantly lower AGE levels and a reduced TNF-α/IL-35 ratio, along with higher levels of IL-35, IL-4, and IL-12, compared to the longer-duration group. Our findings indicate that in youths with uncomplicated T1D, disease duration—not metabolic memory—plays a dominant role in early microvascular alterations. Full article

Enteroviruses (EVs), particularly those within the species Enterovirus A and B, represent a significant global public health burden, especially in infants and young children. While often causing self-limiting hand, foot, and mouth disease (HFMD), certain serotypes can lead to severe neurological and cardiopulmonary complications. This comprehensive review focuses on the major pathogenic serotypes, including enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16), coxsackievirus A6 (CV-A6), coxsackievirus B3 (CV-B3), and enterovirus D68 (EV-D68). We began by reconstructing a phylogenetic tree based on VP1 protein sequences, elucidating the genetic relationships and evolutionary patterns among these serotypes, which underpin their diverse antigenicity and epidemiology. Building upon this genetic foundation, the review then provides a detailed synthesis of their distinct pathogenesis, highlighting the five-phase clinical progression from exanthematous phase to convalescence, and their unique tropisms for target organs such as the central nervous system and heart. Progressing to the molecular mechanisms, a critical component of this work is a systematic summary of the specific host receptors that mediate viral entry, including SCARB2 for EV-A71 and CV-A16, sialic acid and ICAM-5 for EV-D68, and CAR/CD55 for CV-B3, explaining the mechanistic basis for their tissue specificity and pathogenicity. Finally, to translate these insights into clinical applications, we critically evaluate the current landscape of vaccine development, noting the high efficacy (~90%) of inactivated EV-A71 vaccines in Asia and the significant global success of poliovirus vaccines, while also addressing the stark lack of cross-protective or licensed vaccines for other prevalent serotypes like CV-A16, CV-A6, and EV-D68. The review concludes that the high genetic diversity and serotype-specific immunity of enteroviruses pose a major challenge, necessitating a concerted shift towards the development of broad-spectrum vaccines and therapeutics informed by an integrated understanding of viral evolution, receptor usage, and pathogenesis. Full article

Background: Growing evidence highlights the beneficial effects of flavonoids, including anthocyanins, as key components in reducing cardiovascular risk, and emphasizes that incorporating anthocyanin-rich fruits into the daily diet significantly impacts public health. Methods: The effect of bioactive polyphenols from raspberry fruit (RBF) on molecular pathways in inflammation was studied in activated RAW 264.7 macrophages and their protective potential against endothelial dysfunction was analyzed using TNF-α-induced human umbilical vein endothelial cells (HUVECs). Results: The results have shown that RBF extract, along with its anthocyanin and polyphenol fractions, has a significant anti-inflammatory effect in macrophage cell culture by inhibiting the LPS-induced expression of pro-inflammatory genes, including IL-6, IL-1β, TNF-α, and NF-κB. Moreover, RBF and both fractions have demonstrated a protective effect on endothelial function by decreasing the expression of several inflammation-related genes and adhesion molecules, such as IL-6, IL-1β, VCAM-1, ICAM-1, and SELE, in TNF-α-induced HUVECs. Conclusions: The consumption of RBF and/or polyphenol-rich extracts may help prevent the onset of early atherosclerosis. This is attributed to their ability to improve inflammation status and enhance vascular endothelial function. Given the strong anti-inflammatory properties of RBF, incorporating them into a daily diet could significantly reduce the risk of non-communicable diseases related to inflammation. Full article

Malignant cerebral infarction (MCI) is rare but often fatal. Early identification helps guide monitoring and decompressive surgery. This study evaluated whether serum biomarkers add predictive value beyond clinical and imaging data in severe stroke patients with anterior circulation large vessel occlusion (LVO). In this prospective study, 73 acute severe LVO stroke patients underwent whole-brain CT perfusion (CTP) with rCBV-based core measurement at admission and follow-up MRI at 24 ± 12 h for infarct and edema volume assessment. Serum biomarkers (s100b, NSE, VEGF, ICAM1) were sampled a median of 20.5 h after baseline imaging. Logistic regression models predicted MCI using baseline variables (NIHSS, ASPECTS, rCBV < 30%), adding treatment data (rtPA, mTICI, NIHSS posttreatment), and adding serum biomarkers. Performance was assessed by AUC, accuracy, F1, and cross-validated R². MCI occurred in 18/73 (24%) patients. Baseline models showed an AUC of 0.72; adding treatment improved the AUC to 0.88. Biomarkers slightly increased the AUC (0.90) but did not improve F1. Higher s100b was associated with more severe injury but did not enhance the prediction of MCI. Models with baseline imaging and treatment best explained infarct (R² ≈ 0.27) and edema (R² ≈ 0.58). In conclusion, admission severity, CTP, and early treatment response are the main predictors of MCI and aid early risk stratification of patients. Despite their pathophysiologic relevance, serum biomarkers do not add substantial predictive value. Full article

Living kidney transplantation offers the best results for end-stage renal disease patients, but concerns about cardiovascular risk after nephrectomy for kidney donors have been raised. We aimed to estimate the contribution of renal function to endothelial dysfunction (ED) and subclinical inflammation in a non-interventional, prospective, multicenter, longitudinal study with two cohorts: living kidney donors and their transplant recipients (registered clinical trial NCT02515643). The measured glomerular filtration rate (mGFR) by iohexol clearance, estimated GFR according to the CKD-EPI and MDRD-4 formulas, and levels of endothelial dysfunction (sVCAM-1, sICAM-1, E-selectin, von Willebrand Factor, pentraxin, and urinary albumin-to-creatinine ratio) and subclinical inflammation biomarkers (sIL-6, sTNF-R1, sTNF-R2, sTWEAK, and high-sensitivity C-reactive protein) were determined at baseline and 1-year follow-up. Fifty pairs of donors and recipients were recruited between 2015 and 2018. Among the endothelial dysfunction biomarkers, sVCAM-1 increased in donors and decreased in recipients (p < 0.01) while, among the inflammation biomarkers, sTNFR1 and sTNFR2 significantly increased in donors and decreased in recipients (p < 0.001). After transplantation, parallel increases and decreases in ED and subclinical inflammation biomarkers were observed in the donor and recipient cohorts, respectively. Long-term follow-up is needed to characterize the cardiovascular risk associated with these changes. Full article

Background/Objectives: Patients with chronic kidney disease (CKD) face higher risks of infections, poor vaccine responses, and cardiovascular diseases, leading to increased morbidity and mortality due to immune dysfunction and frailty. This study aims to evaluate immune status and frailty in CKD patients across different treatments, examine the influence of frailty on immune status, and link these factors to mortality. Methods: A total of 174 participants were included (end-stage renal disease, ESRD n = 40; hemodialysis, HD n = 40; peritoneal dialysis, n = 36; kidney transplant patients, n = 40; healthy subjects n = 18). Immunophenotyping of lymphocyte and monocyte subpopulations was performed, and frailty was assessed using the Edmonton Frail Scale. Principal component analysis (PCA) integrated immune and frailty variables to define an “immuno-fragile profile,” and survival was monitored for up to six years. Results: CKD patients, especially those on HD, showed decreased lymphocyte counts and proinflammatory monocyte subpopulations with increased expression of costimulatory molecules (B7.2/CD86 and ICAM-1/CD54). Frailty was most prevalent in HD patients (53%), with notable sex differences. PCA identified three components—lymphocyte counts, monocyte co-stimulatory expression, and frailty—that together explained 70% of the variance. Survival analysis revealed that patients with lower lymphocyte counts and higher frailty scores had increased mortality risk, especially in the HD and ESRD groups. Cox regression confirmed that the immuno-fragile profile independently predicted mortality. Conclusions: The integration of immune alterations and frailty defines an immuno-fragile profile strongly associated with mortality in CKD patients, which may serve as a robust prognostic tool to improve risk stratification and guide personalized interventions in clinical practice. Full article

Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is essential for physiological processes such as development and wound healing, but its dysregulation contributes to a range of pathological conditions including cancer, diabetic retinopathy, and chronic inflammation. In recent years, marine-derived compounds have emerged as promising multitarget agents with anti-angiogenic potential. Posidonia oceanica, a Mediterranean seagrass traditionally used in folk medicine, is increasingly recognized for its pharmacological properties, including antioxidant, anti-inflammatory, and anti-invasive activities. This study investigated the effects of a hydroethanolic extract from P. oceanica leaves (POE) on human Endothelial Colony-Forming Cells (ECFCs), a subpopulation of endothelial progenitor cells with high proliferative and vessel-forming capacity, and a relevant model for studying pathological angiogenesis. ECFCs were treated with POE (4–8 µg/mL), and cell viability, morphology, migration, invasion, tube formation, oxidative stress, and activation markers were evaluated. POE did not alter ECFC morphology or viability, as confirmed by Trypan Blue and MTT assays. However, functional assays revealed that POE significantly impaired ECFC migration, invasion, and in vitro angiogenesis in a dose-dependent manner. Under VEGF (Vascular endothelial growth factor) stimulation, POE reduced intracellular ROS accumulation and downregulated key redox-regulating genes (hTRX1, hTRX2, PRDX2, AKR1C1, AKR1B10). Western blot analysis showed that POE inhibited VEGF-induced phosphorylation of KDR, mTOR and p-ERK, while p-AKT remained elevated, indicating selective disruption of VEGF downstream signaling. Furthermore, POE reduced the expression of pro-inflammatory and pro-coagulant markers (VCAM-1, ICAM-1, TF) and partially reversed TNF-α–induced endothelial activation. These findings suggest that POE exerts anti-angiogenic effects through a multitargeted mechanism, supporting its potential as a natural therapeutic agent for diseases characterized by aberrant angiogenesis. Full article