Search Results (141)

Background: Emerging evidence indicates that the liver plays a key role in spinal cord injury (SCI) pathophysiology. Method: This study reanalysed published proteomic datasets from rat models and patients with SCI using bioinformatics and literature/database searches. The aim was to identify liver-specific molecular signatures in SCI blood samples and to link these to severity and neurological recovery at various time points (acute/sub-acute and chronic). Results: Across species, a high proportion of injury severity and neurological recovery-associated proteins were linked to liver function. Notably, non-improvers exhibited prolonged sub-acute proinflammatory responses. These changes were not restricted to classical acute-phase reactants but reflected coordinated alterations in hepatic metabolic and synthetic pathways. Pathway analysis consistently highlighted Liver X Receptor /Retinoic X Receptor (LXR/RXR), complement system/cascade and DHCR24 signalling pathways, with predicted directional changes linked to recovery status. Several proteins were identified and categorised as markers of liver dysfunction, metabolic function, complement/coagulation factors and/or acute-phase proteins. Alpha-2-HS-glycoprotein (AHSG) and afamin (AFM) were commonly dysregulated across species datasets, suggesting conserved roles in inflammation and lipid metabolism. Further associations with liver pathologies such as fibrosis and cirrhosis, particularly in non-improvers, were identified. Conclusion This work builds on emerging evidence of hepatic involvement in SCI by providing cross-species, time-resolved proteomic support for altered liver-associated protein output following injury. Together, these findings underscore the central role of hepatic responses in SCI, highlighting liver-associated proteins and pathways as candidate biomarkers that may aid in stratifying recovery trajectories and informing clinical prognostication. Full article

Natural fungal polysaccharides are increasingly explored as bioactive compounds capable of orchestrating complex regenerative responses during tissue repair. This study aimed to evaluate the in vivo wound-healing efficacy and molecular mechanisms of a topical polysaccharide formulation derived from Bovistella utriformis (Calvatin 2%) using complementary murine, zebrafish, and proteomic approaches. Phylogenetic analysis based on ITS sequences confirmed the taxonomic identity of the Chilean specimen. In a murine full-thickness excisional wound model, Calvatin 2% significantly accelerated wound contraction and re-epithelialization compared to both saline and base-cream controls, achieving near-complete closure by day 10. Label-free quantitative proteomic analysis of wound tissue by UHPLC-HRMS identified 2432 high-confidence proteins, with 171 upregulated and 153 downregulated proteins in the Calvatin versus control comparison (p < 0.01). Functional enrichment revealed strong activation of innate immune response, complement activation, coagulation cascades, and acute-phase response pathways, while lipid metabolism, mitochondrial energy production, and muscle-related processes were significantly downregulated. KEGG pathway analysis further highlighted complement and coagulation cascades and neutrophil extracellular trap formation as the most prominently affected pathways. In a zebrafish laser-induced wound model, Calvatin induced early and sustained regenerative responses, reaching over 93% wound closure by 18 days post-lesion, significantly outperforming both PBS and vehicle-treated groups. Chronic oral administration of polysaccharides did not induce major hepatic inflammatory responses, supporting systemic safety. Overall, these findings indicate that B. utriformis polysaccharides are associated with modulation of immune- and repair-related pathways together with tissue reprogramming processes that may contribute to accelerated cutaneous regeneration, positioning Calvatin as a promising bioactive formulation for wound-healing applications. Full article

Background/Objectives: Trace metal homeostasis is regulated by nutritional status and is crucial for maintaining redox balance, vascular function, and neuroinflammation. Dysregulation of systemic copper (Cu) metabolism, especially an elevated level of non-ceruloplasmin-bound copper (NCC), has been linked to oxidative stress and early cognitive decline. However, the nutritional and molecular pathways that connect Cu imbalance to mild cognitive impairment (MCI) are not well understood. Methods: We compared the serum Cu and zinc levels of individuals with normal cognition (NC; n = 116) and MCI (n = 184). An exploratory serum proteomic analysis using pooled samples was conducted to investigate patterns related to Cu dysregulation. We identified proteins using pattern correlation analysis and then performed a protein–protein interaction analysis using STRING and functional annotation and biological and Kyoto Encyclopedia of Genes and Genomes pathways. Results: The individuals with MCI had higher NCC levels than those with NC, indicating disrupted Cu metabolism influenced by nutrition and metabolism. The proteomic analysis revealed changes in proteins related to lipid transport, metal balance, and inflammation, including transthyretin, transferrin, apolipoprotein A-I, alpha-1 antitrypsin, antithrombin III, and alpha-2-macroglobulin, which respond to oxidative stress and vascular injury. Conclusions: In this cross-sectional analysis of baseline data, NCC levels were associated with cognitive status and specific circulating proteomic profiles. These findings suggest a potential relationship between copper-related biomarkers and mild cognitive impairment; however, longitudinal studies are required to clarify temporal relationships and potential mechanistic pathways. Full article

Background/Objectives: To analyze possible epigenetic changes (miRNA) in systemic lupus erythematosus (SLE) patients on a Mediterranean diet (MD) supplemented with extra virgin olive oil (EVOO). Methods: Fifteen SLE patients with medium/high MD adherence were randomized into an intervention group (IG) (daily supplementation of 40 mL of EVOO for 24 weeks) or to a control group (CG). miRNA profiles from blood peripheral cells were analyzed pre-/post-intervention using next-generation sequencing. Differential expression analysis was performed by DESeq2 in R to determine changes in the log2FC. Functional enrichment analysis was performed using GeneCodis 4. Results: EVOO supplementation resulted in changes in the expression of 16 miRNAs in the IG. Compared to the CG, two miRNAs showed upregulation (miR-451a, miR-1307-5p) while five showed downregulation (miR-193b-50, miR-134-5p, miR1287-5p, miR-124-3p, miR-654-3p). miR-124-3p, which has been proposed to be an SLE biomarker, showed the lowest relative expression after EVOO supplementation (L2FC −3.36; p_unadj = 0.025), whereas miR-1307-5p (L2FC 1.115 p_unadj = 0.02) and miR-451a (L2FC 0.77 p_unadj = 0.036) showed the highest relative abundance. The functional enrichment analysis showed that Th1 and Th2 cell differentiation and the complement/coagulation cascades were among the top ten most significantly enriched pathways. Conclusions: Our data suggest that MD supplementation with EVOO leads to changes in the profile of miRNAs in SLE patients, potentially impacting disease pathogenesis. Further research is needed to validate these preliminary findings and the mechanisms by which EVOO modifies miRNA expression in the context of this disease. Full article

Endothelial cells are key regulators of vascular homeostasis, and their dysfunction plays a central role in the development of atherosclerosis and other cardiovascular diseases. Multinucleated variant endothelial cells (MVECs) have been described in pathological vascular regions; however, their functional properties remain poorly characterized. The aim of the present study was to compare lipid handling, inflammatory activation, barrier-associated features, and secretory profiles of typical endothelial cells (TECs, EA.hy926 line) and MVECs under low-density lipoprotein (LDL) exposure. MVECs were generated by polyethylene glycol-induced fusion of EA.hy926 cells and incubated with LDL under standardized conditions. Intracellular cholesterol accumulation was assessed biochemically, cytokine secretion was quantified by ELISA, gene expression of inflammatory, endothelial, junctional, and vasoactive markers was analyzed by quantitative real-time PCR, and the endothelial secretome was characterized using data-independent acquisition liquid chromatography–tandem mass spectrometry (DIA-LC-MS). MVECs demonstrated enhanced cholesterol accumulation compared with TECs following LDL exposure. At the transcriptional level, MVECs were characterized by elevated basal expression of proinflammatory markers, including IL1B, IL6, and NFKB1, and showed a markedly amplified IL6 and IL8 response to LDL. In parallel, MVECs exhibited reduced expression of genes associated with antioxidant defense (SOD1), barrier integrity (TJP1), and hemostatic function (VWF). Consistent with transcriptional data, mass spectrometry-based secretome analysis revealed decreased secretion of von Willebrand factor (vWF), vascular endothelial growth factor C (VEGFC), and endothelin-1 (EDN1) by MVECs, accompanied by increased secretion of tissue-type plasminogen activator (t-PA). Functional enrichment analysis of secretome-associated proteins highlighted pathways related to extracellular matrix–receptor interaction, focal adhesion, cell adhesion molecules, complement and coagulation cascades, and leukocyte transendothelial migration. In contrast, TECs demonstrated a more pronounced transcriptional response in EDN1, consistent with their role in vascular tone regulation. Immunocytochemical analysis further revealed altered subcellular distribution of the tight junction protein ZO-1 in MVECs, indicating junctional destabilization. Taken together, these results indicate that MVECs represent a distinct endothelial phenotype characterized by enhanced lipid accumulation, sustained proinflammatory activation, altered secretory signaling, and reduced barrier and hemostatic potential. Such features suggest that MVECs may contribute to the maintenance of chronic endothelial dysfunction and vascular inflammation under conditions of lipid overload. Full article

Imperfect first-trimester screening for hypertensive disorders of pregnancy (HDP) means many high-risk women miss the window for preventive aspirin, and the biological heterogeneity of HDPs is overlooked. This study aimed to leverage first-trimester serum proteomics to create a more precise tool for predicting preeclampsia (PE) and differentiating it from other HDPs. A prospective nested case–control study (n = 172) was conducted using targeted liquid chromatography-multiple reaction monitoring-mass spectrometry (LC-MRM-MS) proteomic profiling of 115 proteins. Machine learning (ML) methods were used to develop classifiers from the proteomic data. The signature predictive of PE was characterized by dysregulation of the complement and coagulation cascades (F10, C8A, C1QA, SERPING1, VTN). The profile differentiating gestational hypertension (GAH) from chronic hypertension (CAH) was linked to lipid metabolism (HRG, APOA4, APOC2). An 18-protein support vector machine (SVM) model for predicting PE demonstrated exceptional performance, with 94% sensitivity and 100% specificity, significantly outperforming the standard Fetal Medicine Foundation (FMF) screening algorithm. Pathway analysis confirmed that PE is associated with early activation of innate immunity and coagulation pathways, while GAH is linked to a pregnancy-induced metabolic response. A targeted serum proteomic combined with ML approach represents a new perspective diagnostic tool with strong potential to personalize monitoring for women at the highest risk for specific hypertensive pregnancy complications. Full article

Background: Obesity is a major risk factor for type 2 diabetes (T2D); however, the molecular links between these conditions are not fully understood. Methods: We performed an integrative serum proteomics study on samples from 134 individuals (healthy controls, patients with obesity and/or T2D) using both data-independent (DIA) and data-dependent (DDA) liquid chromatography-mass spectrometry approaches, complemented by phosphopeptide enrichment, kinase activity prediction, network and pathway analyses to get more information on the different proteoforms involved in the pathophysiology of the diseases. Results: We identified 235 serum proteins, including 13 differentially abundant proteins (DAPs) between groups. Both obesity and T2D were characterized by activation of complement and coagulation cascades, as well as alterations in lipid metabolism. Ingenuity Pathway Analysis^® (IPA) revealed shared canonical pathways, while phosphorylation-based regulation differentiated the two conditions. Elevated hemopexin (HPX), vitronectin (VTN), kininogen-1 (KNG1) and pigment epithelium-derived factor (SERPINF1), along with decreased adiponectin (ADIPOQ) and apolipoprotein D (APOD), indicated a pro-inflammatory, pro-coagulant serum profile. Network analyses of antimicrobial and immunomodulatory peptides (AMPs) revealed strong overlaps between immune regulation and lipid metabolism. Phosphoproteomics and kinase prediction highlighted altered CK2 and AGC kinase activities in obesity, suggesting signaling-level modulation. Conclusions: Our comprehensive proteomic and phosphoproteomic profiling reveals overlapping yet distinct molecular signatures in obesity and T2D, emphasizing inflammation, complement activation and phosphorylation-driven signaling as central mechanisms that potentially contribute to disease progression and therapeutic targeting. Full article

Visceral white spot disease caused by Pseudomonas plecoglossicida severely threatens marine aquaculture, highlighting the need for effective control strategies. To clarify the role of a novel small RNA, sRNA0024, in bacterial pathogenicity, we constructed an sRNA0024 deletion mutant (ΔsRNA0024) and compared its phenotype and virulence with those of the wild-type strain NZBD9. In vitro assays showed that deletion of sRNA0024 did not affect bacterial growth but significantly reduced biofilm formation and adhesion. In vivo infection experiments in orange-spotted grouper (Epinephelus coioides) demonstrated that the ΔsRNA0024 mutant had a 3.8-fold higher 50% lethal dose (LD₅₀), improved host survival, and milder splenic lesions than the wild type. Histopathology and host transcriptome analyses revealed weakened activation of complement–coagulation cascades, neutrophil extracellular traps, leukocyte migration, and inflammatory signaling pathways, indicating a lower-intensity immune response. Bacterial transcriptomics showed that deletion of sRNA0024 was associated with reduced luxR expression and attenuated quorum-sensing–associated virulence traits, supporting a possible role for this small RNA in modulating luxR expression and QS-related host immunopathology. These findings identify sRNA0024 as an important contributor to the virulence of P. plecoglossicida and highlight the sRNA0024–luxR module as a potential antivirulence target for controlling visceral white spot disease in aquaculture. Full article

p17, the human immunodeficiency virus type 1 (HIV-1) matrix protein traditionally associated with viral assembly, has been recently investigated for its extracellular functions linked to vascular damage. This review examines the molecular and pathogenic signatures by which p17 and its variants (vp17s) contribute to endothelial activation, aberrant angiogenesis, and vascular inflammation, highlighting their relevance even under effective antiretroviral therapy (ART). Specifically, p17 exerts chemokine-like activities by binding to chemokine (C-X-C motif) receptor-1 and 2 (CXCR-1/2) on endothelial cells (ECs). This interaction triggers key signaling cascades, including the protein kinase B (Akt)-dependent extracellular signal-regulated kinase (ERK) pathway and endothelin-1/endothelin receptor B axis, driving EC motility, capillary formation, and lymphangiogenesis. Variants such as S75X demonstrate enhanced lymphangiogenic potency, associating them with tumorigenic processes involved in non-Hodgkin lymphoma (NHL) pathogenesis. Importantly, p17 promotes endothelial von Willebrand factor (vWF) storage and secretion, implicating a pro-coagulant state that may trigger the increased thromboembolic risks observed in HIV-positive patients. Furthermore, p17 crosses the blood–brain barrier (BBB) via CXCR-2-mediated pathways, contributing to neuroinflammation by activating microglia and astrocytes and amplifying monocyte chemoattractant protein-1 (MCP-1) levels, therefore playing a critical role in the development of HIV-associated neurocognitive disorders. Hence, the elaboration of potential therapeutic strategies finalized at inhibiting p17/vp17s’ interaction with their receptors could complement ART by addressing HIV-related neurovascular morbidity. Full article

Background: Hypospadias is often associated with abnormal prepuce development. Investigating the differences between the inner prepuce of hypospadias patients and normal controls at the transcriptomic level and histological characteristics helps to reveal the causes of its developmental abnormalities or implement targeted treatments. Materials and Methods: Dorsal and ventral inner preputial tissues were collected from 31 hypospadias patients and 21 phimosis children (controls). Differences in gene expression between the two groups were studied via transcriptomic sequencing and enrichment analysis. Corresponding histological features were further validated by histological staining. Results: Transcriptomic sequencing results showed that, compared to the control group, the dorsal inner prepuce of the hypospadias group had 97 upregulated and 10 downregulated genes; the ventral prepuce had 140 upregulated and 99 downregulated genes. Among all upregulated genes, 44 were closely related to fibrosis. Other significantly enriched terms included cornified envelope formation, efferocytosis, C-type lectin receptor signaling pathway, and complement and coagulation cascades. Histological validation revealed that the dorsal inner prepuce of hypospadias children contained more collagen fibers, a higher ratio of type I/III collagen, and lower microvessel density, showing some correlation with the severity of hypospadias. Conclusions: This study demonstrated a hyper-fibrotic state in the inner prepuce of hypospadias, which may significantly impact post-operative wound healing and complications. Full article

Porcine reproductive and respiratory syndrome (PRRS) is a highly contagious epidemic caused by the porcine reproductive and respiratory syndrome virus (PRRSV). Characterized by reproductive disorders in pregnant sows and respiratory symptoms in pigs of all ages, it poses a severe threat to the global swine industry. In recent years, the high mutation rate of PRRSV has increasingly limited the effectiveness of vaccines against it, prompting the search for new anti-PRRSV drugs. scutellarin (SCU), a natural flavonoid compound extracted from the medicinal plant Scutellaria baicalensis, possesses multiple biological activities. Its antiviral effects have been demonstrated in numerous studies; however, its inhibitory activity against PRRSV and the underlying mechanism remain unknown. In this study, through in vitro cell experiments, we found that scutellarin significantly inhibits PRRSV infection in PAMs. Furthermore, it directly acts on PRRSV to exert antiviral effects. Transcriptomic analysis suggests that scutellarin may exert its anti-PRRSV effects by regulating host immunity and anti-inflammation through immune-related signaling pathways, including the complement and coagulation cascades, ECM-receptor interaction, Rap1 signaling pathway, and PI3K-Akt signaling pathway. Full article

Aeromonas veronii is a major pathogen threatening freshwater aquaculture, yet the molecular mechanisms of Pelteobagrus vachellii’s immune response to this infection remain unclear. This study integrated histopathology, mRNA-seq and small RNA-seq to investigate P. vachellii’s response to A. veronii at 48 h post-challenge. Histopathologically, infection induced gill epithelial detachment, hepatocyte swelling with cytoplasmic vacuolation, and melanomacrophage centers (MMCs) in the mid-kidney (histological assessment of the head kidney was not feasible due to sampling limitations associated with its small size). Transcriptomic analysis identified 1210 differentially expressed genes (DEGs) in the head kidney (819 downregulated, 391 upregulated), significantly enriched in 11 immune pathways (e.g., NF-κB, Th17 cell differentiation, Complement and coagulation cascades), with key immune genes (e.g., IL-1β, TCRα, CCL4) upregulated. Gene Set Enrichment Analysis (GSEA) revealed activation of the proteasome, ribosome and oxidative phosphorylation pathways, and suppression of the autophagy-animal, FoxO and AMPK pathways. Small RNA-seq identified 544 known and 958 novel miRNAs in the head kidney, with 42 downregulated and 36 upregulated differentially expressed miRNAs (DE miRNAs). The miRNA-mRNA network showed that DE miRNAs (e.g., miR-101-y/z, miR-132-z, miR-3167-y) negatively regulated immune-related target genes (IL-1R1, IRF4, IκBα) in core immune pathways. Collectively, this study clarifies the pathological and miRNA-mRNA regulatory modules of P. vachellii head kidney against A. veronii infection, providing valuable information that enables the further analyses of the defense mechanisms of P. vachellii against A. veronii infection. Full article

Didelphis aurita is a widely distributed neotropical marsupial frequently found in peri-urban environments and known to harbor various pathogens, including hemoparasites of the genus Hepatozoon. However, the systemic physiological responses of naturally infected individuals remain poorly understood. This study aimed to characterize the serum proteomic profile of Didelphis aurita naturally infected with Hepatozoon sp., providing insights into host–parasite interactions and potential biomarkers of infection. Serum samples were analyzed using liquid chromatography–tandem mass spectrometry (LC-MS/MS), followed by functional annotation based on Gene Ontology and KEGG pathway enrichment. A total of 67 proteins were identified, 33 of which were exclusive to infected animals. The most abundant proteins included albumin, hemoglobin subunits, and venom metalloproteinase inhibitors (DM43 and DM64). Functional enrichment revealed significant involvement in complement and coagulation cascades, protease inhibition, antioxidant defense, and extracellular vesicle localization. Key proteins such as fibrinogen, plasminogen, antithrombin, SERPIN family members, vitronectin, and fibronectin suggest an integrated host response involving hemostasis, inflammation control, and tissue remodeling. This is the first report of the serum proteome of Didelphis aurita naturally infected with Hepatozoon sp. Despite the absence of protein validation, the findings provide novel insights into marsupial immunophysiology and offer a foundation for future biomarker research and ecoimmunological surveillance in synanthropic species. Full article

Grass carp (Ctenopharyngodon idella), a key species in freshwater aquaculture, is particularly vulnerable to opportunistic pathogens, including Aeromonas hydrophila and Aeromonas veronii. While the pathogenic mechanisms of individual infections have been extensively characterized, the host immune responses during co-infection remain poorly understood. This research explored the renal pathological alterations and transcriptomic shifts in grass carp subjected to simultaneous infection by A. hydrophila and A. veronii. Mortality occurred as early as 24 h post-challenge, ultimately reaching a cumulative death rate of 65%. Quantitative analysis of renal bacterial burden revealed a marked increase in colonization at 3 days post-infection (dpi). The histopathological assessment showed progressive kidney damage, including tubular collapse, epithelial necrosis, interstitial edema, and widespread epithelial desquamation, with the most severe lesions observed at 5 dpi and partial signs of recovery by 7 dpi. A total of 1106 and 472 genes were found to be differentially expressed at 1 and 5 dpi, respectively, based on transcriptome profiling. The functional enrichment analysis indicated that the differentially expressed genes (DEGs) were mainly involved in the complement and coagulation cascade pathways. Notably, the immune-related genes exhibited a biphasic trend, with predominant downregulation at 1 dpi followed by marked upregulation by 5 dpi, indicating dynamic changes in immune modulation during co-infection. These results provide new insights into host responses during dual bacterial infections in fish and may inform disease prevention strategies in aquaculture. Full article

(1) Background: IgA nephropathy (IgAN) is a leading cause of chronic kidney disease worldwide. Despite its prevalence, the molecular mechanisms of IgAN remain poorly understood, partly due to limited research scale. Identifying key genes involved in IgAN’s pathogenesis is critical for novel diagnostic and therapeutic strategies. (2) Methods: We identified differentially expressed genes (DEGs) by analyzing public datasets from the Gene Expression Omnibus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to elucidate the biological roles of DEGs. Hub genes were screened using weighted gene co-expression network analysis combined with machine learning algorithms. Immune infiltration analysis was conducted to explore associations between hub genes and immune cell profiles. The hub genes were validated using receiver operating characteristic curves and area under the curve. (3) Results: We identified 165 DEGs associated with IgAN and revealed pathways such as IL-17 signaling and complement and coagulation cascades, and biological processes including response to xenobiotic stimuli. Four hub genes were screened: three downregulated (FOSB, SLC19A2, PER1) and one upregulated (SOX17). The AUC values for identifying IgAN in the training and testing set ranged from 0.956 to 0.995. Immune infiltration analysis indicated that hub gene expression correlated with immune cell abundance, suggesting their involvement in IgAN’s immune pathogenesis. (4) Conclusion: This study identifies FOSB, SLC19A2, PER1, and SOX17 as novel hub genes with high diagnostic accuracy for IgAN. These genes, linked to immune-related pathways such as IL-17 signaling and complement activation, offer promising targets for diagnostic development and therapeutic intervention, enhancing our understanding of IgAN’s molecular and immune mechanisms. Full article