During the development of neural circuits, axons are guided by a variety of molecular cues to navigate through the brain and establish precise connections with correct partners at the right time and place. Many axon guidance cues have been identified and they play pleiotropic roles in not only axon guidance but also axon fasciculation, axon pruning, and synaptogenesis as well as cell migration, angiogenesis, and bone formation. In search of receptors for Sema3E in axon guidance, we unexpectedly found that Plexin B3 is highly expressed in retinal ganglion cells of zebrafish embryos when retinal axons are crossing the midline to form the chiasm. Plexin B3 has been characterized to be related to neurodevelopmental disorders. However, the investigation of its pathological mechanisms is hampered by the lack of appropriate animal model. We provide evidence that Plexin B3 is critical for axon guidance in vivo. Plexin B3 might function as a receptor for Sema3E while Neuropilin1 could be a co-receptor. The intracellular domain of Plexin B3 is required for Semaphorin signaling transduction. Our data suggest that zebrafish could be an ideal animal model for investigating the role and mechanisms of Sema3E and Plexin B3 in vivo.

The Semaphorin family is a group of proteins studied broadly for their functions in nervous systems. They consist of eight subfamilies ubiquitously expressed in vertebrates, invertebrates, and viruses and exist in membrane-bound or secreted forms. Emerging evidence indicates the relevance of semaphorins outside the nervous system, including angiogenesis, cardiogenesis, osteoclastogenesis, tumour progression, and, more recently, the immune system. This review provides a broad overview of current knowledge on the role of semaphorins in the immune system, particularly its involvement in inflammatory and infectious diseases, including chlamydial infections.

Type 2 diabetes mellitus (T2DM) is a disease characterized by a prolonged hyperglycemic condition caused by insulin resistance mechanisms in muscle and liver, reduced insulin production by pancreatic β cells, and a chronic inflammatory state with increased levels of the pro-inflammatory marker semaphorin 3E. Phytochemicals present in several foods have been used to complement oral hypoglycemic drugs for the management of T2DM. Notably, dipeptidyl peptidase IV (DPPIV) inhibitors have demonstrated efficacy in the treatment of T2DM. Our study aimed to investigate, in in vitro models of insulin resistance, the ability of the flavanones naringenin and hesperetin, used alone and in combination with the anti-inflammatory natural molecules curcumin, polydatin, and quercetin, to counteract the insulin resistance and pro-inflammatory molecular mechanisms that are involved in T2DM development. Our results show for the first time that the combination of naringenin, hesperetin, curcumin, polydatin, and quercetin (that mirror the nutraceutical formulation GliceFen®, Mivell, Italy) synergistically decreases expression levels of the pro-inflammatory gene SEMA3E in insulin-resistant HepG2 cells and synergistically decreases DPPIV activity in insulin-resistant Hep3B cells, indicating that the combination of these five phytochemicals is able to inhibit pro-inflammatory and insulin resistance molecular mechanisms and could represent an effective innovative complementary approach to T2DM pharmacological treatment.

Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease whose earliest clinical manifestations are microvascular tone dysregulation and peripheral microcirculatory abnormalities. Following previous evidence of an association between circulating neurovascular guidance molecules and SSc disturbed angiogenesis, here, we measured the levels of soluble neuropilin 1 (sNRP1), semaphorin 3E (Sema3E), and Slit2 by enzyme-linked immunosorbent assay in serum samples from a large case series of 166 SSc patients vs. 110 healthy controls. We focused on their possible correlation with vascular disease clinical features and applied logistic regression analysis to determine which of them could better reflect disease activity and severity. Our results demonstrate that, in SSc: (i) sNRP1 is significantly decreased, with lower sNRP1 serum levels correlating with the severity of nailfold videocapillaroscopy (NVC) abnormalities and the presence of ischemic digital ulcers (DUs); (ii) both Sema3E and Slit2 are increased, with Sema3E better reflecting early NVC abnormalities; and (iii) higher Sema3E correlates with the absence of DUs, while augmented Slit2 associates with the presence of DUs. Receiver operator characteristics curve analysis revealed that both circulating sNRP1 and Sema3E show a moderate diagnostic accuracy. Moreover, logistic regression analysis allowed to identify sNRP1 and Sema3E as more suitable independent biomarkers reflecting the activity and severity of SSc-related peripheral microvasculopathy.

Schwann cells (SCs) play a critical role in peripheral nerve (PN) regeneration because of their ability to proliferate, migrate, and provide trophic support for axon regeneration after PN injury. However, the underlying mechanism is still partially understood. Semaphorin3E (Sema3E), a member of the Sema3s family, is a secreted molecular known as a repelling cue in axon guidance and inhibitor of developmental and postischemic angiogenesis. In this study, we examined the expression of Sema3E in sciatic nerves and SCs and explored the effects of Sema3E on SCs proliferation and migration. Immunofluorescence and ELISA analyses illustrated the expression of Sema3E in SCs of Sciatic nerves and the secretion of Sema3E by cultured SCs, respectively. Exogenous Sema3E promoted SC proliferation and migration while knockdown of the endogenous Sema3E by siRNA transfection attenuated proliferation and migration of SCs. Furthermore, blocking the receptor Neuropilin 1 (Nrp1), PlexinD1 and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) by neutralizing antibody or inhibitor suppressed the promoting effects of Sema3E on SCs. This study indicated that Sema3E promoted SC proliferation and migration and the involvement of receptor PlexinD1, Nrp1, and VEGFR2 in these processes. This study extended our understanding of the mechanism that modulated SC phenotype during nerve injury and provided a potential target for promoting PN regeneration.

We aimed to firstly examine the effects of nutrition and exercise training on irisin, Sema-3E, biochemical and inflammatory parameters in obese patients. This study was conducted using 37 individuals were divided into three groups according to body mass index (BMI) as non-obese, 1nd degree and 2nd degree obese individuals. Nutrition and exercise training were applied to groups for eight weeks. Insulin resistance decreased in non-obese and 1st degree obese subjects. HsCRP values decreased only in the second degree obese individuals. Adiponectin values were significantly decreased in all three groups. There was a negative correlation between serum adiponectin and plasma irisin levels both before and after treatment. Sema-3E levels increased significantly in only the first degree obese individuals, whereas plexin-D1 values did not change significantly in any group. Our findings indicate that nutrition and exercise training we apply improved both anthropometric measurements and biochemical parameters in obese and non-obese individuals.

During angiogenesis, VEGF acts as an attractive cue for endothelial cells (ECs), while Sema3E mediates repulsive cues. Here, we show that the small GTPase RhoJ integrates these opposing signals in directional EC migration. In the GTP-bound state, RhoJ interacts with the cytoplasmic domain of PlexinD1. Upon Sema3E stimulation, RhoJ released from PlexinD1 induces cell contraction. PlexinD1-bound RhoJ further facilitates Sema3E-induced PlexinD1-VEGFR2 association, VEGFR2 transphosphorylation at Y1214, and p38 MAPK activation, leading to reverse EC migration. Upon VEGF stimulation, RhoJ is required for the formation of the holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, thereby preventing degradation of internalized VEGFR2, prolonging downstream signal transductions via PLCγ, Erk, and Akt, and promoting forward EC migration. After conversion to the GDP-bound state, RhoJ shifts from PlexinD1 to VEGFR2, which then terminates the VEGFR2 signals. RhoJ deficiency in ECs efficiently suppressed aberrant angiogenesis in ischemic retina. These findings suggest that distinct Rho GTPases may act as context-dependent integrators of chemotactic cues in directional cell migration and may serve as candidate therapeutic targets to manipulate cell motility in disease or tissue regeneration.

There is emerging evidence that molecules, receptors, and signaling mechanisms involved in vascular development also play crucial roles during the development of the nervous system. Among others, specific semaphorins and their receptors (neuropilins and plexins) have, in recent years, attracted the attention of researchers due to their pleiotropy of functions. Their functions, mainly associated with control of the cellular cytoskeleton, include control of cell migration, cell morphology, and synapse remodeling. Here, we will focus on their roles in the hippocampal formation that plays a crucial role in memory and learning as it is a prime target during neurodegeneration.

Semaphorins were originally discovered as essential mediators involved in regulation of axonal growth during development of the nervous system. Ubiquitously expressed on various organs, they control several cellular functions by regulating essential signaling pathways. Among them, semaphorin3E binds plexinD1 as the primary receptor and mediates regulatory effects on cell migration, proliferation, and angiogenesis considered major physiological and pathological features in health and disease. Recent in vitro and in vivo experimental evidence demonstrate a key regulator role of semaphorin3E on airway inflammation, hyperresponsivenss and remodeling in allergic asthma. Herein, we aim to provide a broad overview of the biology of semaphorin family and review the recently discovered regulatory role of semaphorin3E in modulating immune cells and structural cells function in the airways. These findings support the concept of semaphorin3E/plexinD1 axis as a therapeutic target in allergic asthma.

UNASSIGNED: The migration and proliferation of vascular smooth muscle cells (VSMCs) are crucial events in the neointimal formation, a hallmark of atherosclerosis and restenosis. Semaphorin3E (Sema3E) has been found to be a critical regulator of cell migration and proliferation in many scenarios. However, its role on VSMCs migration and proliferation is unclear. This study aimed to investigate the effect of Sema3E on VSMCs migration, proliferation and neointimal formation, and explore possible mechanisms.
UNASSIGNED: We found that the expression of Sema3E was progressively decreased during neointimal formation in a carotid ligation model. H&E-staining showed lentivirus-mediated overexpression of Sema3E in carotid ligation area attenuated neointimal formation. Immunofluorescence staining showed that the receptor (PlexinD1) of Sema3E was expressed in vascular walls. In cultured mouse VSMCs, Sema3E inhibited VSMCs migration and proliferation via plexinD1 receptor. The inhibitory effect was mediated, at least in part, by inactivating Rap1-AKT signalling pathways in VSMCs. Moreover, we found that PDGFBB down-regulated the expression of Sema3E in VSMCs and Sema3E notably inhibited the expression of PDGFB in endothelial cells. In addition, the number of Sema3E-positive VSMCs was diminished in plaques of atherosclerotic patients. Results from a public GEO microarray database showed a negative correlation between Sema3E and PDGFB transcriptional levels in the human plaques examined.
UNASSIGNED: Our study demonstrates that Sema3E/plexinD1 inhibits proliferation and migration of VSMCs via inactivation of Rap1-AKT signalling pathways. The mutual inhibition between PDGF-BB and Sema3E after vascular injury plays a critical role in the process of neointimal formation.