Search Results (169)

Although the SARS-CoV-2 pandemic no longer poses a global emergency, the virus continues to diversify and acquire immunoevasive properties. Understanding the molecular pathways that shape SARS-CoV-2 pathogenesis has become essential. In this paper, we summarize the most recent current evidence on how the spike protein structurally evolves, on changes in key non-structural proteins, such as nsp14, and on host factors, such as TMPRSS2 and neuropilin-1. These changes, together, shape viral entry, replication fidelity and interferon antagonism. Given the emerging Omicron variants of SARS-CoV-2, recent articles in the literature, cryo-EM analyses, and artificial intelligence-assisted mutational modeling were analyzed to infer and contextualize mutation-driven mechanisms. It is through these changes that the virus adapts and evolves, such as optimizing angiotensin-converting enzyme binding, modifying antigenic surfaces, and accumulating mutations that affect CD8⁺ T-cell recognition. Multi-omics data studies further support SARS-CoV-2 pathogenesis through convergent evidence linking viral adaptation to host immune and metabolic reprogramming, as occurs in myocarditis, liver injury, and acute kidney injury. By integrating proteomic, transcriptomic, and structural findings, this work presents how the virus persists and dictates disease severity through interferon antagonism (ORF6, ORF9b, and nsp1), adaptive immune evasion, and metabolic rewiring. All these insights underscore the need for next-generation interventions that provide a multidimensional framework for understanding the evolution of SARS-CoV-2 and guiding future antiviral strategies. Full article

(1) Background: Ulcerative colitis (UC) is a persistent inflammatory condition of the intestine, characterized by dysregulated T cell-mediated immune responses. Curcumin (CUR), a common food additive and health supplement, is noted for possessing anti-inflammatory and immunomodulatory properties. Nevertheless, the molecular mechanisms underlying its therapeutic effects remain incompletely elucidated. This research aims to investigate the therapeutic mechanisms of CUR in UC, focusing on its role in restoring T cell homeostasis by modulating TIGIT and Neuropilin-1 (NRP1). (2) Methods: We employed a DSS-induced murine colitis model, combined with network pharmacology, molecular docking, protein–protein interaction docking, molecular dynamics simulations, and invitro assays with Jurkat T cells. (3) Results: CUR markedly ameliorated clinical manifestations and histopathology in DSS-treated mice, restoring the balance of T cell and memory T cell subsets. Computational predictions and experimental validation showed that CUR downregulated TIGIT and NRP1 expression in inflamed colonic tissue and directly inhibited their expression in activated T cells invitro. (4) Conclusions: This study reveals a novel immunoregulatory mechanism of this natural compound. These findings suggest CUR modulates TIGIT/NRP1 to inhibit excessive T cell activation and restore immune homeostasis in UC. Full article

Liposomes modified with slightly acidic pH-sensitive peptides (SAPSp-lipo) are effectively delivered to tumor tissues, followed by cellular uptake in the tumor microenvironment. Although SAPSp-lipo can penetrate tumor tissues via the interspace route between cancer cells and the extracellular matrix (ECM), penetration needs to be enhanced to deliver liposomes into tumor cores comprising malignant cancer cells. To enhance the intratumoral penetration of SAPSp-lipo, we focused on the internalizing RGD peptide (iRGD), which can penetrate tumor tissue, differing from the penetration mechanism of SAPSp. In this study, we developed liposomes modified with iRGD-conjugated SAPSp (SAPSp-iRGD-lipo). Compared with SAPSp-lipo, SAPSp-iRGD-lipo was delivered to deeper regions within both spheroids and tumor tissues. The enhanced penetration was suppressed by a co-treatment with a Neuropilin-1 inhibitor, and the fluorescence signals from intratumorally injected SAPSp-iRGD-lipo were localized in Neuropilin-1-expressing regions, indicating a Neuropilin-1-mediated tumor penetration. Moreover, SAPSp-iRGD-lipo reduced F-actin formation in monolayered cells and was not localized in F-actin-rich regions in tumors, suggesting that SAPSp-iRGD-lipo facilitates tumor penetration through actin depolymerization. In addition, anticancer siRNA delivered by SAPSp-iRGD-lipid nanoparticles effectively induced apoptosis in cells under slightly acidic conditions. Taken together, SAPSp-iRGD-modified nanoparticles represent a novel class of tumor-penetrable and microenvironment-responsive drug carriers capable of efficient intratumoral delivery and therapeutic activity. Full article

Myocardial infarction (MI) remains a leading cause of mortality worldwide, yet effective cardioprotective strategies remain limited in clinical settings. Vascular endothelial growth factor B (VEGFB) has emerged as a promising therapeutic candidate in MI, but the role of its co-receptor, Neuropilin-1 (NRP1), in cardiomyocyte (CM) survival under ischemic stress remains poorly understood. Here, we investigated VEGFB-NRP1 signaling using an in vivo zebrafish model of cardiac injury as well as in vitro hypoxia models in CMs. We demonstrated that VEGFB overexpression conferred protection against ischemic injury and enhanced cardiac regeneration in the zebrafish heart. Mechanistically, we showed that VEGFB treatment enhances CM viability through reducing reactive oxygen species (ROS), ferroptosis activation, and preserving mitochondrial integrity. We also demonstrated that NRP1 knockdown in the CMs abolished the VEGFB-mediated protective effects, indicating the significant role of NRP1 signaling in VEGFB-induced cardioprotective effects in MI. Lastly, using transcriptome analysis, we confirmed that VEGFB induces anti-apoptotic and anti-ferroptosis gene programs in CMs in response to hypoxic stress. Collectively, our findings provide mechanistic insight into cell death activation pathways, including ferroptosis, in response to ischemic stress and further validate the therapeutic potential of VEGFB in promoting CM survival in ischemic heart disease. Full article

CD9 protein belongs to a family of proteins called tetraspanins, so named for their four-transmembrane-spanning architectures. These proteins are located in domains in the plasmatic membrane, called tetraspanin-enriched microdomains (TEMs). Several proteases and cellular receptors for virus entry cluster into TEMs, suggesting that TEMs are preferred virus entry portals. Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates virus attachment and entry into cells by binding to human angiotensin-converting enzyme 2 (ACE-2). In addition, the secretory, type-I membrane-bound SARS-CoV-2 S protein is synthesized as a precursor (proS) that undergoes posttranslational cleavages by host cell proteases, such as furin and TMPRSS2. Moreover, it has been shown that neuropilin-1 (NRP1), which is known to bind furin-cleaved substrates, potentiates SARS-CoV-2 infectivity. Our results indicate that CD9 facilitates SARS-CoV-2 infection. In addition, we show how knocking out CD9 leads to a decrease in the expression of NRP1, a protein that improves SARS-CoV-2 infection. Furthermore, we show that CD9 colocalizes with ACE-2, NRP1, furin, and TMPRSS2 at the plasma membrane; that the absence of CD9 decreases the expression of these proteins on the plasma membrane CD9-enriched microdomains, and that CD9 interacts with ACE2. In conclusion, our data suggest that CD9 facilitates SARS-CoV-2 infection and that CD9 brings together different host proteins involved in SARS-CoV-2 attachment and entry into host cells, such as ACE2, NRP1, furin, and TMPRSS2. Importantly, the fact that a blocking antibody targeting CD9 can effectively reduce SARS-CoV-2 titers highlights not only the mechanistic role of CD9 in viral entry but also offers translational potential, suggesting that tetraspanin-targeting antibodies could be developed as therapeutic agents against SARS-CoV-2 and possibly other coronaviruses, with meaningful implications for clinical intervention. Full article

Background/Objectives: Medulloblastoma (MB) is the second leading cause of cancer-related death in children. Its tumor microenvironment (TME) includes endothelial, glial, and immune cells that influence tumor architecture and progression. Neuropilin-1 (NRP1), a co-receptor for semaphorins and vascular endothelial growth factor (VEGF), is expressed in various cell types during oncogenesis, yet its role in MB progression remains unclear. This study aimed to evaluate the expression and localization of NRP1 and glial fibrillary acidic protein (GFAP) in MB tissue. Methods: We analyzed MB tissue samples using immunohistochemistry, immunofluorescence, and quantitative PCR. Samples were stratified by molecular subgroup (WNT, SHH, non-WNT/non-SHH). We assessed NRP1 expression in tumor-associated microglia/macrophages (TAMs) and endothelial cells, as well as GFAP expression in astrocytes and tumor cells. Histopathological correlations and survival analyses were also conducted. Results: NRP1 was consistently expressed by TAMs across all MB molecular subgroups. Tumor vasculature showed strong endothelial NRP1 expression, while perivascular astrocytic coverage was frequently absent. Astrocytic processes exhibited spatial differences according to tumor histology. In SHH-MBs, a subset of tumor cells showed aberrant GFAP expression, which correlated with tumor recurrence or progression. Conclusions: NRP1 and GFAP display distinct expression patterns within the MB microenvironment, reflecting subgroup-specific biological behavior. Endothelial NRP1 positivity combined with limited vascular-astrocytic interaction and aberrant GFAP expression in SHH-MB may contribute to dysregulated angiogenesis and tumor progression. These findings warrant further investigation to explore their prognostic and therapeutic implications. Full article

Sepsis causes millions of deaths each year. Rapid, targeted therapy can reduce mortality rates. Both bacterial and viral pathogens can trigger sepsis, but the utility of commonly used inflammatory markers for differentiation remains controversial. Moreover, little is known about the time courses of alternative inflammatory parameters. The aim of this prospective, two-center observational study was to investigate the differences in the course of soluble Neuropilin-1 (sNRP-1) levels between bacterial and viral sepsis over a 7-day period. To be included, adult patients had to meet the SEPSIS-3 criteria and be diagnosed with either a bacterial or viral pathogen. Immunosuppressed patients were excluded. While IL-6, PCT, and CRP levels decreased consistently over time, sNRP-1 levels remained elevated in the bacterial group throughout the entire ICU stay. PCT (p < 0.001) and CRP (p = 0.016) levels were significantly associated with the course of sNRP-1. The AUC of sNRP-1 was 0.777 for discriminating between bacterial and viral infections on day 1. sNRP-1 remained stable and significantly higher in bacterial than in viral infections. Furthermore, the AUC values for discrimination ranged from acceptable to good, depending on the day of the ICU stay. sNRP-1 may serve as a potential tool to differentiate between bacterial and viral pathogens in sepsis. Full article

Background/Objectives: Neuropilin-1 (NRP1) is a key co-receptor for SARS-CoV-2, complementing the ACE2 receptor. Several investigations have documented highly conserved sequences in this receptor, supporting the implication of NRP1 as a key mediator in SARS-CoV-2 cellular entry mechanisms. Methods: To investigate this hypothesis, we examined 104,737 SARS-CoV-2 genome fastas from GISAID genomic data, corresponding to isolates collected between 2020 and 2025 in Mexico. Specifically, we focused on the RRAR motif, a known furin-binding site for NRP-1 and the binding site for ACE2 with the spike protein. Our analysis revealed high conservation (>98%) of the RRAR domain compared to a rapidly diminishing ACE2-binding domain. A complementary analysis, using Data from Gene Expression Omnibus (GEO, GSE150316), showed that NRP1 expression in lung tissue remains relatively stable, whereas ACE2 displayed high inter-individual variability and lower abundance compared to NRP1. Based on this evidence, we designed two humans–rats NRP1 siRNAs that were tested in vivo using a melittin-induced lung injury model. Results: The RT-PCR assays confirmed an effective NRP1 knockdown, and the siRNA-treated group showed a significant reduction in the lesions severity. These findings highlight NRP1 as a stable and relevant therapeutic target and suggest the protective potential of siRNA-mediated gene silencing. Conclusions: The evidence presented here supports the rational design of NRP1-directed therapies for multiple circulating SARS-CoV-2 variants in Mexico. Full article

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for Coronavirus Disease 2019 (COVID-19), utilizes its spike protein to infect host cells. In addition to angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1), AXL acts as a spike protein receptor and mediates infection, especially in respiratory cells with low ACE2 expression. Angiotensin II (1–8) can be cleaved into shorter peptides within the biological system. Antibody-based binding assays showed that angiotensin II causes a two-fold increase in the binding between the spike protein and AXL, but not ACE2 or NRP1. While a longer peptide, angiotensin I (1–10), did not affect the spike–AXL binding, shorter lengths of angiotensin peptides exhibited enhancing effects. The C-terminal deletions of angiotensin II to angiotensin (1–7) or angiotensin (1–6) resulted in peptides with enhanced activity toward spike–AXL binding with a similar capacity as angiotensin II. In contrast, the N-terminal deletions of angiotensin II to angiotensin III (2–8) or angiotensin IV (3–8) as well as the N-terminal deletions of angiotensin (1–7) to angiotensin (2–7) or angiotensin (5–7) produced peptides with a more potent ability to enhance spike–AXL binding (2.7-fold increase with angiotensin IV). When valine was substituted for tyrosine at position 4 in angiotensin II or when tyrosine at position 4 was phosphorylated, spike–AXL binding was increased, suggesting that modifications to tyrosine trigger enhancement. Angiotensin IV also enhances spike protein binding to ACE2 and NRP1. Thus, angiotensin peptides may contribute to COVID-19 pathogenesis by enhancing spike protein binding and thus serve as therapeutic targets. Full article

Machine learning (ML) algorithms hold the potential to outperform the selection of patients for immunotherapy (ICIs) compared to previous biomarker studies. We analyzed the predictive performance of ML models and compared them to traditional clinical biomarkers (TCBs) in the field of gastrointestinal (GI) cancers. The study has been registered in PROSPERO (number: CRD42023465917). A systematic search of PubMed was conducted to identify studies applying different ML algorithms to GI cancer patients treated with ICIs using tumor RNA gene expression profiles. The outcomes included were response to immunotherapy (ITR) or survival. Additionally, we compared the ML methodology details and predictive power inherent in the published gene sets using 5-fold cross-validation and logistic regression (LR), on an available well-defined ICI-treated metastatic gastric cancer (GC) cohort (n = 45). A set of standard clinical ICI biomarkers (MLH, MSH, and CD8 genes, plus PMS2 and PD-L1)) and de-novo calculated principal components (PCs) of the original datasets were also included as additional points of comparison. Nine articles were identified as eligible to meet the inclusion criteria. Three were pan-cancer studies, five assessed GC, and one studied colorectal cancer (CRC). Classification and regression models were used to predict ICI efficacy. Next, using LR, we validated the predictive power of applied ML algorithms on RNA signatures, using their reported receiver operating characteristics (ROC) analysis area under the curve (AUC) values on a well-defined ICI-treated gastric cancer (GC) dataset (n = 45). In two cases our method has outperformed the published results (reported/LR comparison: 0.74/0.831, 0.67/0.735). Besides the published studies, we have included two benchmarks: a set of TCBs and using principal components based on the whole dataset (PCA, 99% explained variance, 40 components). Interestingly, a study using a selected gene set (immuno-oncology panel) with AUC = 0.83 was the only one that outperformed the TCB (AUC = 0.8) and the PCA (AUC =0.81) results. Cross-validation of the predictive performance of these genes on the same GC dataset and an investigation of their prognostic role on a collated multi-cohort GC dataset of n = 375 resected, or chemotherapy-treated patients revealed that genes mannose-6-phosphate receptor (M6PR), Indoleamine 2,3-Dioxygenase 1 (IDO1), Neuropilin-1 (NRP1), and MAGEA3 performed similarly, or better than established biomarkers like PD-L1 and MSI. We found an immuno-oncology panel with an AUC = 0.83 that outperformed the clinical benchmark or the PC results. We recommend further investigation and experimental validation in the case of M6PR, IDO1, NRP1, and MAGEA3 expressions based on their strong predictive power in GC ITR. Well-designed studies with larger sample sizes and nonlinear ML models might help improve biomarker selections. Full article

Background: The aim of this study was to compare the levels of Neuropilin-1 (NRP-1) in maternal plasma and fetal cord blood plasma between pregnancies complicated by preeclampsia (PE) and those in normotensive pregnant women. Materials and Methods: This prospectively designed study included 53 pregnant women aged 18 years or older and at least 20 weeks into gestation, who were admitted to the Maternity Department of Izmir Katip Çelebi University Atatürk Training and Research Hospital. The patient group consisted of 28 pregnant women who met the diagnostic criteria for PE, while the control group included 25 normotensive pregnant women. The diagnosis of PE was established based on the 2020 diagnostic criteria of the American College of Obstetricians and Gynecologists (ACOG). After detailed anamnesis, blood samples were collected immediately after delivery in EDTA tubes to assess serum NRP-1 levels. These samples included maternal blood, fetal cord blood, and additional tests such as CBC, liver and kidney function tests, serum electrolytes, spot urinalysis, prothrombin time (PT), and activated partial thromboplastin time (APTT). Results: There was a statistically significant difference between the two groups in terms of gestational week, presence of comorbidities, hypertension (HT), diabetes mellitus (DM), history of PE, and protein detected in spot urine examinations. Pregnant women in the PE group had significantly higher rates of comorbidities, HT, and DM compared to the control group (p < 0.001, 0.002, and 0.007, respectively). No statistically significant differences were observed between the two groups regarding hemoglobin, platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), or fetal cord plasma NRP-1 levels (p: 0.736, 0.831, 0.561, and 0.734, respectively). However, a statistically significant difference was found in maternal plasma NRP-1 levels (p: 0.02), which were lower in the control group compared to the PE group (median: 473.3 pg/mL vs. 587.7 pg/mL, respectively). The optimal cut-off value for maternal plasma NRP-1 to predict PE, with the best sensitivity and specificity, was determined to be 358.4 pg/mL. Among the study participants, 40 pregnant women had maternal plasma NRP-1 levels above the cut-off value, while 13 had levels below it. PE occurred significantly more frequently in the high NRP-1 group than in the low group. When demographic and clinical characteristics were analyzed, a statistically significant but weak positive correlation was found between body mass index (BMI) and maternal plasma NRP-1 levels (p: 0.02, Rho: 0.304). No strong or statistically significant relationships were identified with other variables. There was no significant difference in fetal cord plasma NRP-1 levels between the PE group and the normotensive group. In contrast, maternal plasma NRP-1 levels were significantly higher in the PE group. The cut-off value for maternal plasma NRP-1, providing optimal sensitivity and specificity for predicting PE, remained 358.4 pg/mL. Conclusions: While further studies involving larger cohorts of pregnant women from diverse racial backgrounds and various hospitals are needed to better understand the relationship between NRP-1 and PE, maternal NRP-1 concentration shows promise as a diagnostic marker. Full article

Cancers represent a significant global health concern, being among the most prevalent malignancies and contributing substantially to morbidity and mortality rates. Notably, colorectal, gastric, pancreatic, and liver cancers are the most frequently diagnosed among these malignancies. The pathogenesis of gastrointestinal (GI) cancers is multifactorial, encompassing a complex interplay of genetic predispositions, environmental exposures, and lifestyle choices. Despite advances in diagnostic approaches and therapeutic strategies, existing treatment modalities, particularly in the advanced stages of these cancers, remain ineffective. Recent research efforts have increasingly focused on the identification and characterization of novel biomarkers that could enhance both the detection and treatment of gastrointestinal cancers. One particularly promising area of investigation involves neuropilins (NRPs). NRPs are involved in essential biological processes such as angiogenesis, cellular migration, and tumor cell-microenvironment interactions, all of which promote tumor progression and contribute to the development of treatment resistance. Overexpression of neuropilins has been linked to poor prognosis in patients, implying that they could be useful in diagnosis and serve as targets for molecular treatment. Recent research also suggests that inhibiting neuropilin activity may slow tumor growth and inhibit angiogenic processes, opening up new possibilities for targeted therapeutic techniques in the treatment of gastrointestinal malignancies. Full article

In order to find a good candidate for Förster Resonance Energy Transfer (FRET)-mediated X-ray-induced photodynamic therapy (X-PDT) for the treatment of cancer, lanthanide (Ln)-based AGuIX nanoparticles (NPs) conjugated with Rose Bengal (RB) as a photosensitizer (PS) were synthesized. X-PDT overcomes the problem of the poor penetration of visible light into tissues, which limits the efficacy of PDT in the treatment of deep-seated tumors. It is essential to optimize FRET efficiency by maximizing the overlap integral between donor emission and acceptor absorption and lengthening the duration of the donor emission. In this study, we optimized energy transfer between a scintillator (Sc) as a donor and a PS as an acceptor. Terbium (Tb) and Gadolinium (Gd) as Scs and Rose RB as a PS were chosen. The study of energy transfer between Tb, Gd and RB in solution and chelated on AGuIX NPs proved to be FRET-like. RB was conjugated directly onto AGuIX NPs (i.e., AGuIX Ln@RB), and the use of a spacer arm (i.e., AGuIX Ln@spacer arm-RB) increased FRET efficiency. Singlet oxygen production by these NPs was observed under UV–visible illumination and X-ray irradiation. The in vitro bioassay demonstrated 52% cell death of U-251MG derived from human malignant glioblastoma multiforme at a concentration of 1 μM RB after illumination and irradiation (2 Gy, 320 kV, 10 mA, 3 Gy/min at 47 cm). In addition, the RB-coupled NRP-1-targeting peptide (i.e., K(RB)DKPPR) was conjugated onto AGuIX NPs by a thiol-maleimide click chemistry reaction, and an affinity in the nM range was observed. Full article

Neuropilin-1 (NRP1), initially identified as a neuronal guidance protein, has emerged as a multifaceted regulator in cancer biology. Beyond its role in axonal guidance and angiogenesis, NRP1 is increasingly recognized for its significant impact on tumor progression and therapeutic outcomes. This review explores the diverse functions of NRP1 in cancer, encompassing its influence on tumor cell proliferation, migration, invasion, and metastasis. NRP1 interacts with several key signaling pathways, including vascular endothelial growth factor (VEGF), semaphorins, and transforming growth factor-beta (TGF-β), modulating the tumor microenvironment and promoting angiogenesis. Moreover, NRP1 expression correlates with poor prognosis in various malignancies, underscoring its potential as a prognostic biomarker. Therapeutically, targeting NRP1 holds promise as a novel strategy to inhibit tumor growth and enhance the efficacy of regular treatments such as chemotherapy and radiotherapy. Strategies involving NRP1-targeted therapies, including monoclonal antibodies, small molecule inhibitors, and gene silencing techniques, are being actively investigated in preclinical and clinical settings. Despite challenges in specificity and delivery, advances in understanding NRP1 biology offer new avenues for personalized cancer therapy. Although several types of cancer cells can express NRPs, the role of NRPs in tumor pathogenesis is largely unknown. Future investigations are needed to enhance our understanding of the effects and mechanisms of NRPs on the proliferation, apoptosis, and migration of neuronal, endothelial, and cancer cells. The novel frameworks or multi-omics approaches integrate data from multiple databases to better understand cancer’s molecular and clinical features, develop personalized therapies, and help identify biomarkers. This review highlights the pivotal role of NRP1 in cancer pathogenesis and discusses its implications for developing targeted therapeutic approaches to improve patient outcomes, highlighting the role of OMICS in targeting cancer patients for personalized therapy. Full article

Neuropilin-1 is henceforth a relevant target in cancer treatment; however, its way of action remains partly elusive, and the development of small inhibitory molecules is therefore required for its study. Here, we report that two small-sized neuropilin antagonists (NRPa-47 and NRPa-48), VEGF-A₁₆₅/NRP-1 binding inhibitors, are able to decrease VEGF-Rs phosphorylation and to modulate their downstream cascades in the triple-negative breast cancer cell line (MDA-MB-231). Nevertheless, NRPas exert a divergent pathway regulation of MAPK phosphorylation, such as JNK-1/-2/-3, ERK-1/-2, and p38β/γ/δ-kinases, as well as their respective downstream targets. However, NRPa-47 and NRPa-48 apply a common down-regulation of the p38α-kinase phosphorylation and their downstream targets, emphasising its central regulating role. More importantly, none of the 40 selected kinases, including SAPK2a/p38α, are affected in vitro by NRPas, strengthening their specificity. Taken together, NRPas induced cell death by the down-modulation of pro-apoptotic and anti-apoptotic proteins, cell death receptors and adaptors, heat shock proteins (HSP-27/-60/-70), cell cycle proteins (p21, p27, phospho-RAD17), and transcription factors (p53, HIF-1α). In conclusion, we showed for the first time how NRPas may alter tumour cell signalling and contribute to the down-modulation of the cancer therapeutic key factor p38α-kinase phosphorylation. Thus, the efficient association of NRPas and p38α-kinase inhibitor strengthened this hypothesis. Full article