Search Results (37)

Introduction: Psoriasis is an autoimmune systemic disease of not entirely understood pathogenesis. It remains a significant therapeutic challenge and, due to its various comorbidities, has a remarkable detrimental effect on patients’ wellbeing. Semaphorins (Sema) are a group of transmembrane, cell surface-attached and secretory proteins that might play an important role in psoriasis due to their presence on keratinocytes and the ability to stimulate the proinflammatory cytokine production. Aims: The study aimed to assess the concentration of Sema3A, Sema3E, Sema4A, Sema4D and Sema7A in serum samples of psoriatic patients and explore the correlation with disease activity and clinical and metabolic status. Materials and Methods: The study involved 60 patients with plaque psoriasis and 30 healthy volunteers matched for gender, age, and BMI. Results: The mean serum Sema3A, Sema3E and Sema4D levels were significantly higher in patients with psoriasis than controls (p < 0.01, p < 0.05 and p < 0.05, respectively). Contrarily, Sema4A and Sema7A were significantly lower (p < 0.001 and p < 0.05 respectively). Significant positive correlation between Sema3A and UREA was noted. Sema3A levels were significantly higher in moderately ill and overweight patients (p < 0.05, p < 0.01, respectively) and in patients with longer-lasting psoriasis and male patients compared to controls (both p < 0.05). Sema3E significantly negatively correlated with HDL and glucose levels. Sema4A was significantly lower in moderately and severe psoriatic patients (p < 0.0001, p < 0.01, respectively). Sema7A was significantly higher in moderately ill and overweight patients (p < 0.05, p < 0.01, respectively) and significantly lower in male patients and in those with longer lasting disease than in controls. None of the semaphorins correlated with psoriasis severity, total BMI, psoriasis duration and age. Conclusions: Psoriatic patients exhibited distinct alterations in circulating semaphorins, with significantly increased serum Sema3A, Sema3E and Sema4D, and reduced Sema4A and Sema7A compared with healthy subjects. Selected semaphorins demonstrated associations with metabolic parameters and patient characteristics, although none can serve as marker of disease severity. The findings indicate that semaphorins may reflect psoriasis-related systemic disturbances, but further studies are required to explore their potential with disease-associated metabolic or clinical profiles. Full article

Background and Objectives: Semaphorins are immunoregulatory proteins involved in inflammation and neurovascular modulation. Their roles in ischemic stroke pathogenesis and prognosis have recently gained attention. This study aimed to evaluate serum levels of semaphorin 3A, 3F, 4A, 4D, and 7A in patients with acute ischemic stroke and investigate their relationship with disease severity and prognosis. Materials and Methods: A total of 45 patients with acute ischemic stroke and 39 control individuals were enrolled. Serum semaphorin levels were measured using ELISA. Clinical data, including TOAST classification, NIHSS scores, and laboratory parameters, were recorded. Correlations between semaphorin levels and clinical or biochemical variables were analyzed statistically. Results: Semaphorin 4A levels were significantly lower and semaphorin 7A levels significantly higher in the patient group compared to controls (p < 0.001). Semaphorin 7A positively correlated with NIHSS scores (r = 0.390. p = 0.008). Semaphorin 3A and 4A levels showed significant correlations with inflammatory markers and lipid profiles. Semaphorin 3A was higher in female patients. No associations were found with TOAST subtypes or treatment modalities. Five (11.1%) patients died due to stroke-related complications, no significant differences in semaphorin levels were observed between survivors and non-survivors. Conclusions: Semaphorin 3A, 4A, and 7A levels may serve as potential biomarkers for inflammation and disease severity in acute ischemic stroke. Semaphorin 7A, in particular, showed strong prognostic value due to its association with stroke severity. These findings suggest that semaphorins could aid in clinical risk stratification and early intervention planning in ischemic stroke. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a modulator of infection severity, yet its impact on the immune response in severe community-acquired pneumonia (sCAP) remains poorly understood. In this prospective cohort study of 108 adults with sCAP, we evaluated the prevalence and prognostic impact of MASLD and performed pathogen-stratified immune profiling of cytokines and semaphorins on hospital days 1 and 5. MASLD was present in 50% of patients and independently associated with early respiratory failure (OR 3.8) and vasopressor-dependent shock (OR 4.0), despite similar sCAP severity at baseline. MASLD patients exhibited distinct immune profiles, including elevated baseline serum levels of SEMA3A, SEMA7A, IL-2, IL-10, IL-17A, CXCL10, and TGF-β1, and reduced SEMA5A. By day 5, the MASLD group exhibited a greater decline in pro-inflammatory mediators compared to non-MASLD patients but failed to upregulate reparative mediators such as SEMA4D and TGF-β1, unlike the non-MASLD group. These kinetics may suggest a maladaptive immune response in MASLD, potentially consistent with early immune exhaustion. Immunokinetic patterns were pathogen-specific, including transient increase in IL-17A and IL-10 in Legionella and Mycoplasma infections, and CXCL10, IL-2, IL-17A, TGF-β1 and IL-10 in influenza. Serum IL-10, CXCL10, SEMA3F, SEMA4D and SEMA7A correlated with organ failure and sCAP complications. These findings underscore the clinical importance of the lung–liver axis and suggest that semaphorins could serve as valuable prognostic biomarkers for identifying high-risk patients. Full article

Vascular calcification is a critical pathological hallmark of cardiovascular diseases. Although previous studies have indicated that M1 macrophages significantly promote calcification, the exact underlying mechanisms remain unclear. This study examined whether semaphorin 4D (Sema4D), a class IV semaphorin involved in atherosclerosis development, is secreted by M1 macrophages and contributes to the calcification of vascular smooth muscle cells (VSMCs). We observed elevated expression and secretion of Sema4D in both M1 and M2 macrophages, with significantly higher levels in M1-polarized cells. M1 macrophages promoted VSMC calcification in both co-culture and conditioned medium systems, as evidenced by increased alkaline phosphatase activity, enhanced calcium deposition, and upregulation of osteogenic markers. Notably, neutralization of Sema4D in M1 conditioned medium using pepinemab, an anti-Sema4D antibody, effectively attenuated VSMC calcification induced by M1 macrophages. Conversely, supplementation of conditioned medium with recombinant Sema4D enhanced calcification and osteogenic signaling in VSMCs, further supporting the pro-calcifying role of Sema4D. Collectively, these findings highlight macrophage-derived Sema4D as a pivotal regulator of vascular calcification and a promising therapeutic target. Full article

CD100/SEMA4D, a member of the Semaphorin family, is a transmembrane glycoprotein that regulates neurogenesis, immune modulation, and angiogenesis, with its immunoregulatory roles having attracted considerable attention. It is dynamically expressed on the surface of diverse immune cells—including T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells—with expression levels modulated by cellular activation states. CD100 exists in two functional forms: membrane-bound CD100 (mCD100) and soluble CD100 (sCD100) generated via proteolytic cleavage. Recent studies have highlighted its critical involvement in viral infectious diseases. This review systematically summarizes the molecular characteristics, expression patterns, and regulatory functions of CD100 on different immune cells, and discusses its role in viral infectious diseases and its clinical application potential. Full article

Granulosa cell (GC) differentiation, stimulated by FSH and LH, drives oocyte maturation and follicle development. FSH promotes GC proliferation, and LH triggers ovulation. In clinical practice, hCG is used to mimic LH. Despite various controlled ovarian stimulation (COS) protocols employing exogenous gonadotropins and GnRH analogs to prevent premature ovulation, their effectiveness and safety remain debated. To identify markers predicting a positive treatment response, the secretome of gonadotropin-stimulated GC using the human granulosa-like tumor cell line (KGN) via proteomics was analyzed. Additionally, a novel 2D-FFT quantitative method was employed to assess cytoskeleton fiber aggregation and polymerization, which are critical processes for GC differentiation. Furthermore, the activation of key kinases, focal adhesion kinase (FAK), and Rho-associated coiled-coil-containing protein kinase 1 (ROCK-1), which are implicated in cytoskeleton dynamics and hormone signaling, was evaluated. The proteomic analysis revealed significant modulation of proteins involved in extracellular matrix organization, steroidogenesis, and cytoskeleton remodeling. Notably, the combined FSH/hCG treatment led to a dynamic upregulation of the semaphorin pathway, specifically semaphorin 7A. Finally, a significant reorganization of the cytoskeleton network and signaling was detected. These findings enhance our understanding of folliculogenesis and suggest potential novel molecular markers for predicting patient responses to gonadotropin stimulation. Full article

Metal 3D printing is increasingly being used to manufacture titanium–aluminum–vanadium (Ti6Al4V) implants. In vitro studies using 2D substrates demonstrate that the osteoblastic differentiation of bone marrow stromal cells (MSCs) on Ti6Al4V surfaces, with a microscale/nanoscale surface topography that mimics an osteoclast resorption pit, involves non-canonical Wnt signaling; Wnt3a is downregulated and Wnt5a is upregulated, leading to the local production of BMP2 and semaphorin 3A (sema3A). In this study, it was examined whether the regulation of MSCs in a 3D environment occurs by a similar mechanism. Human MSCs from two different donors were cultured for 7, 14, or 21 days on porous (3D) or solid (2D) constructs fabricated by powder-bed laser fusion. mRNA and secretion of osteoblast markers, as well as factors that enhance peri-implant osteogenesis, were analyzed, with a primary focus on the Wnt family, sema3A, and microRNA-145 (miR-145) signaling pathways. MSCs exhibited greater production of osteocalcin, latent and active TGFβ1, sema3A, and Wnt16 on the 3D constructs compared to 2D, both of which had similar microscale/nanoscale surface modifications. Wnt3a was reduced on 2D constructs as a function of time; Wnt11 and Wnt5a remained elevated in the 3D and 2D cultures. To better understand the role of Wnt16, cultures were treated with rhWnt16; endogenous Wnt16 was blocked using an antibody. Wnt16 promoted proliferation and inhibited osteoblast differentiation, potentially by reducing production of BMP2 and BMP4. Wnt16 expression was reduced by exogenous Wnt16 in 3D cells. Addition of the anti-Wnt16 antibody to the cultures reversed the effects of exogenous Wnt16, indicating an autocrine mechanism. Wnt16 increased miR-145-5p, suggesting a potential feedback mechanism. The miR-145-5p mimic increased Wnt16 production and inhibited sema3A in a 3D porous substrate-specific manner. Wnt16 did not affect sema3A production, but it was reduced by miR-145-5p mimic on the 3D constructs and stimulated by miR-145-5p inhibitor. Media from 7-, 14-, and 21-day cultures of MSCs grown on 3D constructs inhibited osteoclast activity to a greater extent than media from the 2D cultures. The findings present a significant step towards understanding the complex molecular interplay that occurs in 3D Ti6Al4V constructs fabricated by additive manufacturing. In addition to enhancing osteogenesis, the 3D porous biomimetic structure inhibits osteoclast activities, indicating its role in modulating bone remodeling processes. Our data suggest that the pathway mediated by sema3A/Wnt16/miR145-5p was enhanced by the 3D surface and contributes to bone regeneration in the 3D implants. This comprehensive exploration contributes valuable insights to guide future strategies in implant design, customization, and ultimately aims at improving clinical outcomes and successful osseointegration. Full article

In sepsis, a balanced pro-inflammatory and anti-inflammatory response results in the bacterial clearance and resolution of inflammation, promoting clinical recovery and survival. Semaphorins, a large family of secreted and membrane-bound glycoproteins, are newly recognized biomarkers and therapeutic targets in immunological and neoplastic disorders. Although semaphorins might also be a crucial part of host defense responses to infection, their role in sepsis is yet to be determined. This study aimed to analyze the association of serum semaphorin concentrations with sepsis severity and outcomes. Serum semaphorin concentrations (SEMA3A, SEMA3C, SEMA3F, SEMA4D, and SEMA7A) were measured in 115 adult patients with community-acquired sepsis and 50 healthy controls. While SEMA3A was decreased, SEMA3C, SEMA3F, SEMA4D, and SEMA7A were increased in sepsis patients. All analyzed SEMA showed good accuracy in identifying patients with sepsis. SEMA kinetics were related to sepsis complications; SEMA3A, SEMA3C, SEMA3F, and SEMA4D with respiratory failure; SEMA3C and SEMA7A with acute kidney injury; and SEMA3C and SEMA3F were related to septic shock. Importantly, SEMA3A, SEMA3C, SEMA4D, and SEMA7A were associated with 28-day mortality. In conclusion, we provide evidence that semaphorins are associated with sepsis course and outcomes. Full article

Semaphorins are an immunoregulatory protein family. Plexins bind semaphorins (SEMAs) and can form receptor complexes that give them chemotactic capacity. The role and expression profile of semaphorins and plexins in inflammatory bowel disease (IBD) is currently unknown. Aim: Characterize the semaphorins and plexins gene and protein expression in intestinal tissue from IBD patients and correlate them with the clinical phenotype. Material and Methods: This comparative and cross-sectional study enrolled 54 diagnosed IBD patients and 20 controls. Gene and protein expression of semaphorins and plexins were determined by RT-PCR and IHQ for the co-localization with neutrophils (myeloperoxidase, MPO) or CD123 plasmacytoid dendritic cells in intestinal tissue from IBD patients. Results: Colonic mucosa from active and remission ulcerative colitis (UC) had a significantly lower SEMA4D and PLXNA1, but higher PLXNB1 gene expression than the control group. The only significant difference between active UC and remission was observed in the higher gene expression of SEMA6D in remission. It was associated with histological remission (p = 0.01, OR = 15, 95% CI: 1.39–16.1). The low expression of PLXNA1 was associated with mild intermittent activity with two relapses per year (p = 0.003, OR = 0.05, CI = 0.006–0.51). Higher SEMA4D+ positive cells were detected in the submucosa, while PLXNC1+/MPO+ in the mucosal and submucosa of active UC patients compared with controls. Conclusions: The increased expression of the semaphorin and plexin family in IBD patients suggests their immunoregulatory function and is associated with remission and clinical phenotype in patients with UC. Full article

Semaphorins (SEMAs), ADAM, and ADAMTS family members are implicated in various cancer progression events within the tumor microenvironment across different cancers. In this study, we aimed to evaluate the expression of SEMA7A, SEMA4D, ADAM8, and ADAMTS10 in colorectal cancer (CRC) in relation to the mutational landscape of KRAS, NRAS, BRAF, PIK3CA, and AKT genes, microsatellite instability (MSI) status, and clinicopathological features. We also examined the associations between the expression of these proteins and selected cytokines, chemokines, and growth factors, assessed using a multiplex assay. Protein concentrations were quantified using ELISA in CRC tumors and tumor-free surgical margin tissue homogenates. Gene mutations were evaluated via RT-PCR, and MSI status was determined using immunohistochemistry (IHC). GSEA and statistical analyses were performed using R Studio. We observed a significantly elevated expression of SEMA7A in BRAF-mutant CRC tumors and an overexpression of ADAM8 in KRAS 12/13-mutant tumors. The expression of ADAMTS10 was decreased in PIK3CA-mutant CRC tumors. No significant differences in the expression of the examined proteins were observed based on MSI status. The SEMA7A and SEMA4D expressions were correlated with the expression of numerous cytokines associated with various immune processes. The potential immunomodulatory functions of these molecules and their suitability as therapeutic targets require further investigation. Full article

The aim of this study was to identify single-nucleotide polymorphisms (SNPs) in bone remodeling-related genes associated with disease severity and bone mineral density (BMD) in early arthritis (EA) patients. For this purpose, the genotyping of 552 SNPs located in gene regions of semaphorins 4b, 4d, 4f, DKK1, 2 and 3, sclerostin, OPG, RANK and RANKL was performed using Immunochip from Illumina Inc. in 268 patients from the Princesa Early Arthritis Register Longitudinal (PEARL) study. Measurements of BMD and disease activity were chosen as outcome variables to select SNPs of interest. The relationships of SNPs with the BMD of the forearm, lumbar spine and hip (Hologic-4500 QDR) were analyzed by linear regression adjusted for age, sex, body mass index and presence of anti-citrullinated peptide antibodies (ACPAs). The association of each SNP with activity variables was analyzed by linear regression, logistic regression or ordered logistic regression according to the variable, and multivariate models were adjusted for potentially confounding variables, such as age, sex and presence of ACPAs. These analyses showed that four SNPs located in the genes coding for RANK (TNFRSF11A) and OPG (TNFRSF11B) were significantly associated with clinical variables of severity. SNP rs1805034 located in exon 6 of TNFRSF11A, which causes a non-synonymous (A/V) mutation, showed significant association with BMD and therefore may be considered as a possible biomarker of severity in RA patients. SNPs in the OPG gene showed an association with serum OPG levels and predicted disease activity after two years of follow-up. Full article

The incidence of bladder cancer worldwide in the last three decades has been increasing in both men and women. So far, there is no established non-invasive bladder cancer biomarker in daily clinical practice. Semaphorin 6D (sema6D) is a transmembrane protein that belongs to the class VI semaphorins. The aim of this study was to evaluate for the first time the potential role of sema6D in bladder cancer. The study group consisted of 40 patients with non-muscle-invasive bladder cancer (NMIBC) and the control group of 20 patients without malignancies. There was a statistically significantly higher urinary sema6D concentration in patients than controls (p < 0.05) but no significant difference in plasma 6D. There were no statistically significant differences in urinary or plasma concentration of sema6D between low- or high-grade cancer and according to the tumor stage in TNM classification. There was a statistically significant negative correlation between plasma sema6D and age of patients (R = −0.6; p = 0.019). Plasma sema6D does not seem to be useful in the clinical practice at this point. However, the urinary sema6D concentration could potentially serve as a marker of NMIBC used for diagnostic purposes, monitoring, and early relapse detection or the assessment of the treatment efficacy. Urinary sema6D is probably not associated with the grading or staging of NMIBC, so it cannot be used for the prediction of disease prognosis. Full article

Semaphorin 4D (Sema4D), also known as CD100, is a multifunctional transmembrane protein with immunoregulatory functions. Upon the activation of immune cells, soluble Semaphorin 4D (sSema4D) is proteolytically cleaved from the membrane by metalloproteinases. sSema4D levels are elevated in various (auto-)inflammatory diseases. Our aim was to investigate sSema4D levels in association with sepsis and critical illnesses and to evaluate sSema4D’s potential as a prognostic biomarker. We measured sSema4D levels in 192 patients upon admission to our medical intensive care unit. We found similar levels of sSema4D in 125 patients with sepsis compared to 67 non-septic patients. sSema4D levels correlated with leukocytes but not with other markers of systemic inflammation such as C-reactive protein or procalcitonin. Most interestingly, in a subgroup of patients suffering from pre-existing liver cirrhosis, we observed significantly higher levels of sSema4D. Consistently, sSema4D was also positively correlated with markers of hepatic and cholestatic injury. Our study suggests that sSema4D is not regulated in sepsis compared to other causes of critical illness. However, sSema4D seems to be associated with hepatic injury and inflammation. Full article

According to recent evidence, some groups of semaphorins (SEMAs) have been associated with cancer progression. These proteins are able to modulate the cellular signaling of particular receptor tyrosine kinases (RTKs) via the stimulation of SEMA-specific coreceptors, namely plexins (plexin-A, -B, -C, -D) and neuropilins (Np1, Np2), which share common domains with RTKs, leading to the coactivation of the latter receptors. MET, ERBB2, VEGFR2, PFGFR, and EGFR, among others, represent acknowledged targets of semaphorins that are often associated with tumor progression or poor prognosis. In particular, higher expression of SEMA6 family proteins in cancer cells and stromal cells of the cancer niche is often associated with enhanced tumor angiogenesis, metastasis, and resistance to anticancer therapy. Notably, high SEMA6 expression in malignant tumor cells such as melanoma, pleural mesothelioma, gastric cancer, lung adenocarcinoma, and glioblastoma may serve as a prognostic biomarker of tumor progression. To date, very few studies have focused on the mechanisms of transmembrane SEMA6-driven tumor progression and its underlying interplay with RTKs within the tumor microenvironment. This review presents the growing evidence in the literature on the complex and shaping role of SEMA6 family proteins in cancer responsiveness to environmental stimuli. Full article

Semaphorins have recently been recognized as crucial modulators of immune responses. In the pathogenesis of COVID-19, the activation of immune responses is the key factor in the development of severe disease. This study aimed to determine the association of serum semaphorin concentrations with COVID-19 severity and outcomes. Serum semaphorin concentrations (SEMA3A, -3C, -3F, -4D, -7A) were measured in 80 hospitalized adult patients with COVID-19 (moderate (n = 24), severe (n = 32), critical, (n = 24)) and 40 healthy controls. While SEMA3C, SEMA3F and SEMA7A serum concentrations were significantly higher in patients with COVID-19, SEMA3A was significantly lower. Furthermore, SEMA3A and SEMA3C decreased with COVID-19 severity, while SEMA3F and SEMA7A increased. SEMA4D showed no correlation with disease severity. Serum semaphorin levels show better predictive values than CRP, IL-6 and LDH for differentiating critical from moderate/severe COVID-19. SEMA3F and SEMA7A serum concentrations were associated with the time to recovery, requirement of invasive mechanical ventilation, development of pulmonary thrombosis and nosocomial infections, as well as with in-hospital mortality. In conclusion, we provide the first evidence that SEMA3A, SEMA3C, SEMA3F and SEMA7A can be considered as new biomarkers of COVID-19 severity. Full article