Bone remodeling is the balance between osteoblasts and osteoclasts. Bone diseases such as osteoporosis and osteoarthritis are associated with imbalanced bone remodeling. Skeletal injury leads to limited motor function and pain. Neurophilin was initially identified in axons, and its various ligands and roles in bone remodeling, angiogenesis, neuropathic pain and immune regulation were later discovered. Neurophilin promotes osteoblast mineralization and inhibits osteoclast differentiation and its function. Neuropolin-1 provides channels for immune cell chemotaxis and cytokine diffusion and leads to pain. Neuropolin-1 regulates the proportion of T helper type 17 (Th17) and regulatory T cells (Treg cells), and affects bone immunity. Vascular endothelial growth factors (VEGF) combine with neuropilin and promote angiogenesis. Class 3 semaphorins (Sema3a) compete with VEGF to bind neuropilin, which reduces angiogenesis and rejects sympathetic nerves. This review elaborates on the structure and general physiological functions of neuropilin and summarizes the role of neuropilin and its ligands in bone and cartilage diseases. Finally, treatment strategies and future research directions based on neuropilin are proposed.

Neuropilin-1 (NRP1) is a transmembrane glycoprotein expressed by several cell types including, neurons, endothelial cells (ECs), smooth muscle cells, cardiomyocytes and immune cells comprising macrophages, dendritic cells and T cell subsets. Since NRP1 discovery in 1987 as an adhesion molecule in the frog nervous system, more than 2300 publications on PubMed investigated the function of NRP1 in physiological and pathological contexts. NRP1 has been characterised as a coreceptor for class 3 semaphorins and several members of the vascular endothelial growth factor (VEGF) family. Because the VEGF family is the main regulator of blood and lymphatic vessel growth in addition to promoting neurogenesis, neuronal patterning, neuroprotection and glial growth, the role of NRP1 in these biological processes has been extensively investigated. It is now established that NRP1 promotes the physiological growth of new vessels from pre-existing ones in the process of angiogenesis. Furthermore, several studies have shown that NRP1 mediates signalling pathways regulating pathological vascular growth in ocular neovascular diseases and tumour development. Less defined are the roles of NRP1 in maintaining the function of the quiescent established vasculature in an adult organism. This review will focus on the opposite roles of NRP1 in regulating transforming growth factor β signalling pathways in different cell types, and on the emerging role of endothelial NRP1 as an atheroprotective, anti-inflammatory factor involved in the response of ECs to shear stress.

Introduction: Breast cancer poses a significant global challenge, prompting researchers to explore novel approaches for potential treatments. Material and Methods: For in vitro study we used thin layer chromatography (TAC) for phytochemical screening, total antioxidant capacity (TLC) assay for antioxidant capacity, and hemolytic activity test for toxicity of Neuropilins (NRPs). We performed bioinformatic analyses to predict protein structures, molecular docking, pharmacophore modeling, and virtual screening to reveal interactions with oncogenes. We conducted 200 ns Molecular Dynamics (MD) simulations and MMGBSA calculations to assess the complex dynamics and stability. Results: We identified phytochemical constituents in Nigella sativa leaves, including tannins, saponins, steroids, and cardiac glycosides, while phlobatannins and terpenoids were absent. The leaves contained 9.4% ± 0.04% alkaloids and 1.9% ± 0.05% saponins. Methanol extract exhibited the highest yield and antioxidant capacity, with Total Flavonoid Content at 127.51 ± 0.76 mg/100 g and Total Phenolic Content at 134.39 ± 0.589 mg GAE/100 g. Hemolysis testing showed varying degrees of hemolysis for different extracts. In-silico analysis indicated stable Neuropilin complexes with key signaling pathways relevant for anti-cancer therapy. Molecular docking scores at different possesses (0, C-50, C -80, C-120,C -150, C -200 ns) revealed strong hydrogen bonding in the complexes and showed -12.9, -11.6, and -11.2 binding Affinities (kcal/mol) to support their stability. Our MD simulations analysis at 200ns confirmed the stability of Neuropilin complexes with the signaling pathways protein PI3K. The calculated binding free energies using MMGBSA provided valuable quantitative information on ligand potency on different time steps. These findings highlight the potential health benefits of N. sativa leaves and their possible role in anti-cancer treatments targeting angiogenesis. Conclusion: Nigella sativa leaves have shown significant medical potential due to their bioactive compounds, which exhibit strong properties in supporting organogenic processes related to cancer. Furthermore, studies have highlighted the promising role of neuropilins in anticancer treatment, demonstrating stable interactions and potential as targeted therapy specifically for breast cancer.

Pancreatic cancer is a major cause of demise worldwide. Although key associated genetic changes have been discovered, disease progression is sustained by pathogenic mechanisms that are poorly understood at the molecular level. In particular, the tissue microenvironment of pancreatic adenocarcinoma (PDAC) is usually characterized by high stromal content, scarce recruitment of immune cells, and the presence of neuronal fibers. Semaphorins and their receptors, plexins and neuropilins, comprise a wide family of regulatory signals that control neurons, endothelial and immune cells, embryo development, and normal tissue homeostasis, as well as the microenvironment of human tumors. We focus on the role of these molecular signals in pancreatic cancer progression, as revealed by experimental research and clinical studies, including novel approaches for cancer treatment.

Autism spectrum disorder (ASD) is a pervasive disorder that most frequently manifests in early childhood and lasts for their entire lifespan. Several behavioural traits characterise the phenotype of patients with ASD, including difficulties in reciprocal social communication as well as compulsive/repetitive stereotyped verbal and non-verbal behaviours. Although multiple hypotheses have been proposed to explain the aetiology of ASD and many resources have been used to improve our understanding of ASD, several aspects remain largely unexplored. Class 3 semaphorins (SEMA3) are secreted proteins involved in the organisation of structural and functional connectivity in the brain that regulate synaptic and dendritic development. Alterations in brain connectivity and aberrant neuronal development have been described in some patients with ASD. Mutations and polymorphisms in SEMA3A and alterations in its receptors and signalling have been associated with some neurological disorders such as schizophrenia and epilepsy, which are comorbidities in ASD, but also with ASD itself. In addition, SEMA3A is a key regulator of the immune response and neuroinflammatory processes, which have been found to be dysregulated in mothers of children who develop ASD and in affected patients. In this review, we highlight neurodevelopmental-related processes in which SEMA3A is involved, which are altered in ASD, and provide a viewpoint emphasising the development of strategies targeting changes in the SEMA3A signal to identify patterns of anomalies distinctive of ASD or to predict the prognosis of affected patients.

The traditional immune checkpoint blockade therapy benefits some patients with cancer, but elicits no response in certain cancers, such as pancreatic adenocarcinoma (PAAD); thus, novel checkpoints and effective targets are required. Here, we found that there was a higher Neuropilin (NRP) expression in tumor tissues as novel immune checkpoints, which was associated with poor prognosis and pessimistic responses to immune checkpoint blockade therapy. In the tumor microenvironment of PAAD samples, NRPs were widely expressed in tumor, immune and stromal cells. The relationship of NRPs with tumor immunological features in PAAD and pan-cancer was evaluated using bioinformatics methods; it was positively correlated with the infiltration of myeloid immune cells and the expression of most immune checkpoint genes. Bioinformatics analysis, in vitro and in vivo experiments suggested that NRPs exhibit potential immune-related and immune-independent pro-tumor effects. NRPs, especially NRP1, are attractive biomarkers and therapeutic targets for cancers, particularly PAAD.

Cancer therapy continues to be a huge challenge as most chemotherapeutic agents exert serious adverse effects on healthy organs. Chemotherapeutic agents lack selective targeting and even the existing target specific therapies are failing due to poor distribution into the tumor microenvironment. Nanotechnology offers multiple advantages to address the limitations encountered by conventional therapy. However, the delivery of nanotherapeutics to tumor tissue has not improved over the years partly due to the poor and inadequate distribution of nanotherapeutics into deeper tumor regions resulting in resistance and relapse. To curb the penetration concerns, iRGD was explored and found to be highly effective in improving the delivery of cancer nanomedicine. The preclinical observations are highly encouraging; however, the clinical translation is at a nascent stage. Based on this, we have made an elaborative effort to give a detailed account of various promising applications of iRGD to increase anticancer and tumor imaging potential. Importantly, we have comprehensively discussed the shortcomings and uncertainties associated with the clinical translation of iRGD-based therapeutic approaches and future directions.

Secreted semaphorin 3F (Sema3F) and semaphorin 3A (Sema3A) exhibit remarkably distinct effects on deep layer excitatory cortical pyramidal neurons; Sema3F mediates dendritic spine pruning, whereas Sema3A promotes the elaboration of basal dendrites. Sema3F and Sema3A signal through distinct holoreceptors that include neuropilin-2 (Nrp2)/plexinA3 (PlexA3) and neuropilin-1 (Nrp1)/PlexA4, respectively. We find that Nrp2 and Nrp1 are S-palmitoylated in cortical neurons and that palmitoylation of select Nrp2 cysteines is required for its proper subcellular localization, cell surface clustering, and also for Sema3F/Nrp2-dependent dendritic spine pruning in cortical neurons, both in vitro and in vivo. Moreover, we show that the palmitoyl acyltransferase ZDHHC15 is required for Nrp2 palmitoylation and Sema3F/Nrp2-dependent dendritic spine pruning, but it is dispensable for Nrp1 palmitoylation and Sema3A/Nrp1-dependent basal dendritic elaboration. Therefore, palmitoyl acyltransferase-substrate specificity is essential for establishing compartmentalized neuronal structure and functional responses to extrinsic guidance cues.

Semaphorins are regulatory molecules that are linked to the modulation of several cancer processes, such as angiogenesis, cancer cell invasiveness and metastasis, tumor growth, as well as cancer cell survival. Semaphorin (SEMA) activity depends on the cancer histotypes and their particularities. In broad terms, the effects of SEMAs result from their interaction with specific receptors/co-receptors - Plexins, Neuropilins and Integrins - and the subsequent effects upon the downstream effectors (e.g. PI3K/AKT, MAPK/ERK). The present article serves as an integrative review work, discussing the broad implications of semaphorins in cancer, focusing on cell proliferation/survival, angiogenesis, invasion, metastasis, stemness, and chemo-resistance/response whilst highlighting their heterogeneity as a family. Herein, we emphasized that semaphorins are largely implicated in cancer progression, interacting with the tumor microenvironment components. Whilst some SEMAs (e.g. SEMA3A, SEMA3B) function widely as tumor suppressors, others (e.g. SEMA3C) act as pro-tumor semaphorins. The differences observed in terms of the biological structure of SEMAs and the particularities of each cancer histotypes require that each semaphorin be viewed as a unique entity, and its roles must be researched accordingly. A more in-depth and comprehensive view of the molecular mechanisms that promote and sustain the malignant behavior of cancer cells is of utmost importance.

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide and is characterized by complex molecular carcinogenesis. Neuropilins (NRPs) NRP1 and NRP2 are the receptors of multiple proteins involved in key signaling pathways associated with tumor progression. We aimed to systematically review all the available findings on their role in HCC. We searched the Scopus, Web of Science (WOS), PubMed, Cochrane and Embase databases for articles evaluating NRPs in preclinical or clinical HCC models. This study was registered in PROSPERO (CRD42022349774) and include 49 studies. Multiple cellular and molecular processes have been associated with one or both NRPs, indicating that they are potential diagnostic and prognostic biomarkers in HCC patients. Mainly NRP1 has been shown to promote tumor cell survival and progression by modulating several signaling pathways. NRPs mainly regulate angiogenesis, invasion and migration and have shown to induce invasion and metastasis. They also regulate the immune response and tumor microenvironment, showing a crucial interplay with the hypoxia response and microRNAs in HCC. Altogether, NRP1 and NRP2 are potential biomarkers and therapeutic targets, providing novel insight into the clinical landscape of HCC patients.