Search Results (288)

Background: Angiosarcomas (ASs) represent a heterogeneous and highly aggressive subset of tumors that respond poorly to systemic treatments and are associated with short progression-free survival (PFS) and overall survival (OS). The aim of this study was to develop and validate an immune-related prognostic model—termed the AS score—using data from two independent sarcoma cohorts. Methods: A prognostic model was developed using a previously characterized cohort of 25 angiosarcoma samples. Candidate genes were identified via the Maxstat algorithm (Maxstat v0.7-25 for R), combined with log-rank testing. The AS score was then computed by weighing normalized gene expression levels according to Cox regression coefficients. For external validation, transcriptomic data from TCGA Sarcoma cohort (n = 253) were analyzed. The Immunoscore—which reflects the tumor immune microenvironment—was inferred using the ESTIMATE package (v1.0.13) in R. All statistical analyses were performed in RStudio (v 4.0.3). Results: Four genes—IGF1R, MAP2K1, SERPINE1, and TCF12—were ultimately selected to construct the prognostic model. The resulting AS score enabled the classification of angiosarcoma cases into two prognostically distinct groups (p = 0.00012). Cases with high AS score values, which included both cutaneous and non-cutaneous forms, exhibited significantly poorer outcomes, whereas cases with low AS scores were predominantly cutaneous. A significant association was observed between the AS score and the Immunoscore (p = 0.025), with higher Immunoscore values found in high-AS score tumors. Validation using TCGA sarcoma cohort confirmed the prognostic value of both the AS score (p = 0.0066) and the Immunoscore (p = 0.0029), with a strong correlation between their continuous values (p = 2.9 × 10⁻⁸). Further survival analysis, integrating categorized scores into four groups, demonstrated robust prognostic significance (p = 0.00021). Notably, in tumors with a low Immunoscore, AS score stratification was not prognostic. In contrast, among cases with a high Immunoscore, the AS score effectively distinguished outcomes (p < 0.0001), identifying a subgroup with poor prognosis but potential sensitivity to immunotherapy. Conclusions: This combined classification using the AS score and Immunoscore has prognostic relevance in sarcoma, suggesting that angiosarcomas with an immunologically active microenvironment (high Immunoscore) and poor prognosis (high AS score) may be prime candidates for immunotherapy and this approach warrants prospective validation. Full article

Background: Short-chain fatty acids (SCFAs), microbial metabolites also known as postbiotics, are essential for maintaining gut health. However, their antiproliferative effects on gastric cancer cells and potential interactions with conventional therapies remain underexplored. This study aimed to investigate the effects of three SCFA salts—magnesium acetate (A), sodium propionate (P), and sodium butyrate (B)—individually and in combination (APB), as well as in combination with dexamethasone (Dex), on AGS gastric adenocarcinoma cells. Methods: AGS cells were treated with PB, AP, AB, APB, Dex, and APB+Dex. Cell viability was assessed to determine antiproliferative effects, and the IC₅₀ of APB was calculated. Flow cytometry was used to evaluate apoptosis and necrosis. Reactive oxygen species (ROS) levels were measured to assess oxidative stress. Proteomic analysis via LC-MS was performed to identify differential protein expression and related pathways impacted by the treatments. Results: SCFA salts showed significant antiproliferative effects on AGS cells, with APB exhibiting a combined IC₅₀ of 568.33 μg/mL. The APB+Dex combination demonstrated strong synergy (combination index = 0.76) and significantly enhanced growth inhibition. Both APB and APB+Dex induced substantial apoptosis (p < 0.0001) with minimal necrosis. APB alone significantly increased ROS levels (p < 0.0001), while Dex moderated this effect in the combination group APB+Dex (p < 0.0001). Notably, the APB+Dex treatment synergistically targeted multiple tumour-promoting mechanisms, including the impairment of redox homeostasis through SLC7A11 suppression, and inhibition of the haemostasis, platelet activation network and NF-κB signalling pathway via downregulation of NFKB1 (−1.34), exemplified by increased expression of SERPINE1 (1.99) within the “Response to elevated platelet cytosolic Ca²⁺” pathway. Conclusions: These findings showed a multifaceted anticancer mechanism by APB+Dex that may collectively impair cell proliferation, survival signalling, immune modulation, and tumour microenvironment support in gastric cancer. Full article

Alzheimer’s Disease (AD) is a multifactorial process. Amyloid plaque formation constitutes the main characteristic of the disease. Despite the identification of numerous factors associated with AD, the mechanism remains unclear in several aspects. Disturbances in intestinal and blood–brain barrier (BBB) penetration, observed in AD, may facilitate immunologic response to food-derived antigens. In the present study, antibodies against egg albumin, bovine-casein, and N-Glycolyl-Neuraminic acid (Neu5Gc) were measured in the cerebrospinal fluid (CSF) and serum of the patients using an enzyme-linked immunosorbent assay (ELISA). Zero anti-Neu5Gc and low concentrations of anti-casein antibodies were detected. Increased anti-native egg albumin antibodies were present in the serum of patients of all stages with 65% positivity (p < 0.001) in mild disease and a higher percentage in females (81.9%, p < 0.001). Lower serum positivity to anti-denatured egg albumin antibodies was observed, showing a gradual increase with severity and higher prevalence also in females. In the CSF, anti-native and anti-denatured egg albumin antibodies were mainly observed in severely ill patients with accumulative positivity to either antigen, reaching 61.8% in severe vs. 15% in mild disease (p < 0.001). Increased values were mainly observed in males. Anti-egg albumin antibodies may be implicated in the disease mechanism through sequence/structural similarity with human proteins, mainly serpins, and it would be worth consideration in further investigations and therapeutic strategies. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently become the leading cause of chronic liver disease and can progress to hepatocellular carcinoma (HCC) through multiple pathogenic mechanisms. Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor activated by proteases such as trypsin, tryptase or coagulation factors VII and Xa. Recent studies have shown that PAR2 expression is increased in the liver of patients with MASLD or liver fibrosis. Its activation is linked to metabolic dysfunction through several pathways, including SREBP1c activation, AMPK inhibition and Akt-induced insulin resistance. Inhibition of PAR2 has been effective in reducing MASLD progression in different animal models. Notably, PAR2 blockade has also been effective in more advanced stages of the disease by dampening chronic inflammation and fibrogenesis through the inhibition of hepatic stellate cell activation and of TGF-β and SerpinB3 production. PAR2 also plays a role in cancer development, promoting tumour proliferation, angiogenesis and expression of immune checkpoint inhibitors (like PD-L1, CD47 and CD24). Due to its multifaceted involvement in liver disease, PAR2 is emerging as a key therapeutic target in this clinical context. This review aims to summarise current knowledge on PAR2′s role in MASLD and its potential as a therapeutic target. Full article

This review highlights recent findings on the potent anti-angiogenic serpin protein, pigment epithelium-derived factor (PEDF) as it relates to metabolic disease, diabetes, angiogenesis and cardiovascular disease (CVD), listing a majority of all the publicly available studies reported to date. PEDF is involved in various physiological roles in the body, and when awry, it triggers various disease states clinically. Biomarkers such as insulin, AMP-activated protein kinase alpha (AMPK-α), and peroxisome proliferator-activated receptor gamma (PPAR-γ) are involved in PEDF effects on metabolism. Wnt, insulin receptor substate (IRS), Akt, extracellular signal-regulated kinase (ERK), and mitogen-activated protein kinase (MAPK) are implicated in diabetes effects displayed by PEDF. For CVD, oxidised LDL, Wnt/β-catenin, and reactive oxygen species (ROS) are players intertwined with PEDF activity. The review also presents an outlook on where efforts could be devoted to bring this serpin closer to clinical trials for these diseases and others in general. Full article

Cutaneous wound healing is a complex process involving multiple cellular and molecular events, and current treatments often face limitations in efficacy and safety. Stem-cell therapy, particularly using mesenchymal stem cells (MSCs), has emerged as a promising approach to enhance wound repair through both direct cell replacement and paracrine signaling. This study investigates the therapeutic potential of human chorionic villus mesenchymal stem cells (hCV-MSCs) and their secretory factors in enhancing cutaneous wound healing. Utilizing a rat model, we combined the local administration of hCV-MSC-laden PEGDA/SA/Col-I hydrogel with the systemic delivery of their secretome, aiming to leverage the complementary mechanisms of cellular and cell-free therapies. Our findings demonstrate that hCV-MSCs delivered via PEGDA/SA/Col-I hydrogel significantly accelerated wound closure compared to controls, with near-complete closure observed by day 20. Histological analysis revealed enhanced keratinocyte maturation (increased KRT10/KRT14 ratio) and a higher density of CD31⁺ blood vessels, indicating improved re-epithelialization and angiogenesis. A mass spectrometry analysis of the hCV-MSC secretome identified 849 proteins, with enrichment in pathways related to ECM organization, cell adhesion, and immune regulation. Key proteins such as ANXA1, SERPINE1, and WNT5A were implicated in wound-healing processes. Combination therapy with systemic secretome administration further accelerated wound closure and enhanced collagen deposition, keratinocyte maturation, and vascularization compared to hCV-MSCs alone. Our results highlight the promising application of hCV-MSCs and their secretome in cutaneous wound healing, paving the way for innovative therapeutic strategies that integrate both local and systemic regenerative approaches. Full article

Background: Hypoxia and immune components significantly shape the tumor microenvironment and influence prognosis and immunotherapy response in gastric cancer (GC). This study aimed to develop hypoxia- and immune-related gene signatures for prognostic evaluation in GC. Methods: Transcriptomic data from TCGA-STAD were integrated with hypoxia- and immune-related genes from InnateDB and MSigDB. A prognostic gene signature was constructed using Cox regression analyses and validated on an independent GSE84437 cohort and single-cell RNA dataset. We further analyzed immune cell infiltration, molecular characteristics of different risk groups, and their association with immunotherapy response. Single-cell RNA-seq data from the TISCH database were used to explore gene expression patterns across cell types. Results: Five genes (TGFB3, INHA, SERPINE1, GPC3, SRPX) were identified. The risk score effectively stratified patients by prognosis, with the high-risk group showing lower overall survival and lower T-cell expression. The gene signature had an association with immune suppression, ARID1A mutation, EMT features, and poorer response to immunotherapy. Gene signature, especially SRPX was enriched in fibroblasts. Conclusions: We developed a robust hypoxia- and immune-related gene signature that predicts prognosis and may help guide immunotherapy strategies for GC patients. Full article

Background: SERPINE1, also known as plasminogen activator inhibitor (PAI), has been proposed as a potential blood biomarker for the early detection and diagnosis of Alzheimer’s disease (AD). Expanding on previous studies, this research contrasted SERPINE1 levels in CSF and brain tissue of AD patients and those at risk for AD with established AD biomarkers. Methods: Utilizing OLINK and immunoassay methods, CSF SERPINE1 protein levels were quantified across two separate cohorts: PREVENT-AD and ADNI. Microarray and RNAseq were used to measure tissue SERPINE1 mRNA levels in two separate cohorts: the Douglas-Bell Canada Brain Bank and the Mayo Clinic Brain Bank. Results: At the pre-clinical stage, elevated CSF levels of pTau, tTau and synaptic markers, alongside reduced hippocampal volume, correlate with CSF SERPINE1 levels. Elevated cortical SERPINE1 mRNA levels in autopsy-confirmed AD show weak correlation with regional plaques and tangles densities, but strong correlation with Braak staging. Conclusions: CSF SERPINE1 levels can be used as an early biomarker for the detection of pathological changes associated with AD. Higher SERPINE1 levels correlate more strongly with tau pathology than with amyloid formation or deposition. Full article

This review highlights recent findings on the versatile serpin protein, pigment epithelium-derived factor (PEDF), in relation to cancer diagnosis, treatment and prognosis. PEDF was initially discovered in the eye but has since been reported to be relevant to various biological roles in the body, and when awry, to clinically lead to various disease states such as neoplasia. At the preclinical stage, potent effects have been reported in studies focussing on apoptosis, metastasis, oxidative stress, immune stimulation and metabolism. Apart from full-length proteins, short peptides based on PEDF have shown promise against cancer. For diagnosis and prognosis, PEDF levels in tumour specimens or in circulation have the potential to serve as biomarkers, most probably in combination with other biomarkers of cancer initiation and progression. Lastly, this review discusses the growing list of studies that point out the perceived pro-cancerous effects of PEDF, though this is clearly outweighed by the anticancer publications. Thus, this review provides a comprehensive and balanced listing of the oncological studies associated with this protein to date, drawing conclusions on whether this potent antiangiogenic protein and its peptides can be used in the future for better cancer treatment, especially against metastasis. Full article

Heparin, a widely used polysaccharidic anticoagulant of animal origin, is associated with risks of contamination and adverse effects, notably bleeding and thrombocytopenia. These limitations have prompted interest in alternative sulfated polysaccharides with anticoagulant properties and improved safety profiles. This study explored the anticoagulant potential of two marine bacterial exopolysaccharides (EPS), infernan and diabolican. It assessed whether chemical modifications (depolymerization, oversulfation) could enhance their anticoagulant properties compared to unfractionated and low molecular weight heparins. Native EPS were depolymerized to generate different molecular weights and then chemically oversulfated to increase negative charge density. Anticoagulant activities were evaluated using clotting and thrombin generation assays (TGA). Molecular docking was performed to model interactions with antithrombin and heparin cofactor II. Only highly sulfated derivatives significantly prolonged activated partial thromboplastin time while showing negligible effect on thrombin time and anti-factor Xa activity. They present different structures, and their binding to antithrombin is not achieved via the classic pentasaccharide motif. In TGA, these derivatives inhibited thrombin formation at higher doses than heparin but induced a marked delay in clot generation. Docking analyses supported their ability to bind serpins, albeit with lower specificity than heparin. Their limited anti-Xa activity and non-animal origin position them as promising anticoagulant candidates. Full article

Porcine reproductive and respiratory syndrome (PRRS) is aworldwide spread disease. This study analyzed the changes in saliva analytes of pigs infected with PRRS virus (PRRSV) in different clinical conditions that can appear in PRRSV-positive farms. Biomarkers for inflammation (haptoglobin, total proteins), immune response (adenosine deaminase), tissue damage (lactate dehydrogenase), stress (alpha-amylase), and sepsis (calprotectin, aldolase, Serpin B12) were measured in pigs under three clinical scenarios: (1) no evident clinical signs, (2) clinical signs indicating PRRSV activation, and (3) secondary bacterial infection by Streptococcus suis. Haptoglobin and lactate dehydrogenase showed significant increases in pigs with PRRSV activation compared to pigs without clinical signs. Additionally, the levels of Serpin B12, aldolase, calprotectin, total proteins, and the activity of adenosine deaminase significantly increased in pigs with meningitis compared to pigs without clinical signs, but did not show significant differences between healthy pigs and those with PRRSV clinical signs without bacterial infection. In summary, PRRSV-infected pigs can show differences in selected saliva analytes depending on their clinical condition. These findings may have practical applications for detecting PRRSV infections and differentiating cases with associated meningitis. Full article

Background/Objectives: An increasing number of studies are exploring how stress influences the development of various psychiatric and physical disorders. Psychological coping strategies and defense mechanisms play a vital role in managing stress. However, the biological mechanisms involved in coping with stress have not been thoroughly researched. This study focuses on the relationships between plasma levels of tPA-BDNF pathway proteins and their correlations with coping strategies and defense mechanisms. Methods: The study involved 48 healthy young adults. All participants completed the self-reported Defense Style Questionnaire (DSQ-40) and Coping Orientation to Problems Experienced Inventory (COPE). BDNF, proBDNF, t-plasminogen activator/tPA, total serpin E1/PAI-1, serpin F2/alpha 2-antiplasmin, and MMP-9 plasma concentrations were determined using ELISA. Results: We detected higher BDNF and lower MMP-9 levels in females. We found differences in the DSQ-40 humor subdimension and in the COPE focus on and venting of emotions category between women and men. We found correlations between studied protein plasma concentrations. Positive correlations of total serpin E1/PAI-1 with denial and mental disengagement and negative correlations with some active coping categories were found. Correlations of DSQ-40 scores with BDNF, proBDNF, MMP-9, and total serpin E1/PAI-1 were detected. Conclusions: Our findings indicate that there are functional associations between the proteins we studied and various coping styles, as well as mature, immature, and neurotic defense mechanisms. Full article

Pear psylla (Cacopsylla chinensis), a major pear tree pest widely distributed in China, is increasingly affecting the productivity of orchards. This species exhibits seasonal polyphenism with two distinct forms, namely, a summer form and a winter form. Through topically applying Beauveria bassiana conidial suspensions to the abdominal cuticle of C. chinensis, we demonstrated that the entomopathogenic fungus B. bassiana exhibits significant yet phenotypically divergent virulence against these two forms. Using PacBio SMRT sequencing and Illumina RNA-seq, we analyzed transcriptomic changes post-infection, revealing form-specific immune responses, with 18,232 and 5027 differentially expressed genes identified in summer- and winter-form pear psylla, respectively, and a total of 3715 DEGs shared between the two seasonal phenotypes. In summer-form individuals, B. bassiana infection disrupted oxidative phosphorylation and downregulated immune recognition genes, cellular immune-related genes, and signaling genes, along with the upregulation of the immune inhibitor serpin, indicating immunosuppression. Conversely, in winter-form individuals, immune-related genes and glycolytic rate-limiting enzymes were upregulated after infection, suggesting that the winter-form immune system normally responds to B. bassiana infection and supports efficient defense through metabolic reprogramming to fuel energy-demanding defenses. These findings advance our understanding of C. chinensis/B. bassiana interactions, providing a basis for elucidating immune regulation in seasonally polymorphic insects. The results also inform strategies to optimize B. bassiana-based biocontrol, contributing to sustainable pear psylla management. Full article

The ichneumonid parasitoid Campoletis chlorideae is an important natural enemy of lepidopteran pests in different agro-ecosystems, specifically targeting early larvae (second- and third-instar). Enhancing the survival of C. chlorideae, especially within hosts, remains a significant technical challenge for large-scale indoor reproduction. This study investigates the use of endogenous serpin-e protein, derived from the host Helicoverpa armigera (Haserpin-e), to improve the survival rate of C. chlorideae in indoor reproduction. The results demonstrated that Haserpin-e protein significantly enhanced cocoon production in C. chlorideae, with no observable adverse effects on the life history traits of both F0 and F1 generations of C. chlorideae. By investigating the mechanism underlying cocoon formation promotion, it was found that Haserpin-e protein reduced the encapsulation, inhibited melanization, as well as suppressed the expression of antimicrobial proteins (AMPs) in H. armigera. This study provides novel insights into improving the survival of C. chlorideae by inhibiting host immune responses through the application of its endogenous Haserpin-e protein during large-scale indoor reproduction efforts. Additionally, this research further elucidates the multifaceted functionality of Haserpin-e proteins by demonstrating their role in regulating innate immune processes in H. armigera, including negatively regulating encapsulation, melanization, and AMP expression. Full article

Bacterial extracellular vesicles (BEVs) produced by members of the intestinal microbiota can not only contribute to digestion but also mediate microbe–host cell communication via the transfer of functional biomolecules to mammalian host cells. An unresolved question is which host factors and conditions influence BEV cargo and how they impact host cell function. To address this question, we analysed and compared the proteomes of BEVs released by the major human gastrointestinal tract (GIT) symbiont Bacteroides thetaiotaomicron (Bt) in vivo in fed versus fasted animals using nano-liquid chromatography with tandem mass spectrometry (LC-MSMS). Among the proteins whose abundance was negatively affected by fasting, nine of ten proteins of the serine protease family, including the regulatory protein dipeptidyl peptidase-4 (DPP-4), were significantly decreased in BEVs produced in the GITs of fasted animals. Strikingly, in extracellular vesicles produced by the intestinal epithelia of the same fasted mice, the proteins with the most increased abundance were serine protease inhibitors (serpins). Together, these findings suggest a dynamic interaction between GI bacteria and the host. Additionally, they indicate a regulatory role for the host in determining the balance between bacterial serine proteases and host serpins exported in bacterial and host extracellular vesicles. Full article