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OBJECTIVE: The dysregulation of the axon guidance pathway is common in pancreatic ductal adenocarcinoma (PDAC), yet our understanding of its biological relevance is limited. Here, we investigated the functional role of the axon guidance cue SEMA3A in supporting PDAC progression. DESIGN: We integrated bulk and single-cell transcriptomic datasets of human PDAC with in situ hybridisation analyses of patients tissues to evaluate SEMA3A expression in molecular subtypes of PDAC. Gain and loss of function experiments in PDAC cell lines and organoids were performed to dissect how SEMA3A contributes to define a biologically aggressive phenotype. RESULTS: In PDAC tissues, SEMA3A is expressed by stromal elements and selectively enriched in basal-like/squamous epithelial cells. Accordingly, expression of SEMA3A in PDAC cells is induced by both cell-intrinsic and cell-extrinsic determinants of the basal-like phenotype. In vitro, SEMA3A promotes cell migration as well as anoikis resistance. At the molecular level, these phenotypes are associated with increased focal adhesion kinase signalling through canonical SEMA3A-NRP1 axis. SEMA3A provides mouse PDAC cells with greater metastatic competence and favours intratumoural infiltration of tumour-associated macrophages and reduced density of T cells. Mechanistically, SEMA3A functions as chemoattractant for macrophages and skews their polarisation towards an M2-like phenotype. In SEMA3Ahigh tumours, depletion of macrophages results in greater intratumour infiltration by CD8+T cells and better control of the disease from antitumour treatment. CONCLUSIONS: Here, we show that SEMA3A is a stress-sensitive locus that promotes the malignant phenotype of basal-like PDAC through both cell-intrinsic and cell-extrinsic mechanisms.

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Osteoarthritis (OA) is characterised by the deterioration of cartilage in the joints and pain. We hypothesise that semaphorin‐3A (sema‐3A), a chemorepellent for sensory nerves, plays a role in joint degradation and pain. We used the mechanical joint loading (MJL) model of OA to investigate sema‐3A expression in the joint and examine its association with the development of OA and pain. We also analyse its effect on chondrocyte differentiation using the ATDC5 cell line. We demonstrate that sema‐3A is present in most tissues in the healthy joint and its expression increases in highly innervated tissues, such as cruciate ligaments, synovial lining and subchondral bone, in loaded compared to nonloaded control joints. In contrast, sema‐3A expression in cartilage was decreased in the severe OA induced by the application of high loads. There was a significant increase in circulating sema‐3A, 6 weeks after MJL compared to the nonloaded mice. mRNA for sema‐3A and its receptor Plexin A1 were upregulated in the dorsal root ganglia of mice submitted to MJL. These increases were supressed by zoledronate, an inhibitor of bone pain. Sema‐3A was expressed at all stages of Chondrocyte maturation and, when added exogenously, stimulated expression of markers of chondrocyte differentiation. This indicates that sema‐3A could affect joint tissues distinctively during the development of OA. In highly innervated joint tissues, sema‐3A could control innervation and/or induce pain‐associated neuronal changes. In cartilage, sema‐3A could favour its degeneration by modifying chondrocyte differentiation. Significance statement: Semaphorin‐3A (sema‐3A) is an axon guidance molecule previously shown to play a role in neural ingrowth and vascularisation during degeneration of tissues. We investigated its expression in tissues of the mouse joint and examined changes in expression with the development of osteoarthritis (OA). We show that sema‐3A expression is increased in highly innervated joint tissues with OA and may control innervation in these tissues. In contrast, sema‐3A expression in cartilage decreases with the severity of OA. We also demonstrate using a chondrocytic cell line that sema‐3A stimulates expression of markers of chondrocyte differentiation and may play a role in cartilage degeneration. [ABSTRACT FROM AUTHOR]

Abstract Background Neural stem cells (NSCs) derived from the embryonic spinal cord are excellent candidates for the cellular regeneration of lost neural cells after spinal cord injury (SCI). Semaphorin 3 A (Sema3A) is well known as being implicated in the major axon guidance of the growth cone as a repulsive function during the development of the central nervous system, yet its function in NSC transplantation therapy for SCI has not been investigated. Here, we report for the first time that embryonic spinal cord-derived NSCs significantly express Sema3A in the SCI environment, potentially facilitating inhibition of cell proliferation after transplantation. Methods siRNA-Sema3A was conjugated with poly-l-lysin-coated gold nanoparticles (AuNPs) through a charge interaction process. NSCs were isolated from embryonic spinal cords of rats. Then, the cells were embedded into a dual-degradable hydrogel with the siRNA- Sema3A loaded-AuNPs and transplanted after complete SCI in rats. Results The knockdown of Sema3A by delivering siRNA nanoparticles via dual-degradable hydrogels led to a significant increase in cell survival and neuronal differentiation of the transplanted NSCs after SCI. Of note, the knockdown of Sema3A increased the synaptic connectivity of transplanted NSC in the injured spinal cord. Moreover, extracellular matrix molecule and functional recovery were significantly improved in Sema3A-inhibited rats compared to those in rats with only NSCs transplanted. Conclusions These findings demonstrate the important role of Sema3A in NSC transplantation therapy, which may be considered as a future cell transplantation therapy for SCI cases. Graphical Abstract

Variants in the high confident autism spectrum disorder (ASD) gene ANK2 target both ubiquitously expressed 220 kDa ankyrin-B and neurospecific 440 kDa ankyrin-B (AnkB440) isoforms. Previous work showed that knock-in mice expressing an ASD-linked Ank2 variant yielding a truncated AnkB440 product exhibit ectopic brain connectivity and behavioral abnormalities. Expression of this variant or loss of AnkB440 caused axonal hyperbranching in vitro, which implicated AnkB440 microtubule bundling activity in suppressing collateral branch formation. Leveraging multiple mouse models, cellular assays, and live microscopy, we show that AnkB440 also modulates axon collateral branching stochastically by reducing the number of F-actin-rich branch initiation points. Additionally, we show that AnkB440 enables growth cone (GC) collapse in response to chemorepellent factor semaphorin 3 A (Sema 3 A) by stabilizing its receptor complex L1 cell adhesion molecule/neuropilin-1. ASD-linked ANK2 variants failed to rescue Sema 3A-induced GC collapse. We propose that impaired response to repellent cues due to AnkB440 deficits leads to axonal targeting and branch pruning defects and may contribute to the pathogenicity of ANK2 variants.

Purpose: To evaluate serum semaphorin 3A (Sema3A) and interleukin 6 (IL-6) levels in pseudoexfoliation syndrome (PXS) patients to determine whether these mediators play a role in the systemic manifestations of PXS. Methods: This prospective case–control study included 70 patients divided into PXS (n = 30) and a control group (n = 40). Serum Sema3A and IL-6 levels were analyzed using the enzyme-linked immunosorbent assay. Results: The PXS group had a statistically higher IL-6 level [3.6(0.64–100) pg/mL], compared to the control group [2.1(0.41–39.93) pg/mL] (p < 0.05). On the other hand, the Sema3A level of the PXS group was lower at [21.55(13.2–67.5) ng/mL] compared to the control group at [29.05(11.5–103.3) ng/mL] (p < 0.05). In the PXS group, there was no correlation between the participants' IL-6 values and Sema3A, age, and body mass index (BMI) (r = 0.153, 0.000, − 0.103, respectively, all, p > 0.05), and between Sema3A values and age and BMI values (r = 0.048, − 0.133, respectively, all, p > 0.05). In the control group, there was no correlation between the participants' IL-6 values and Sema3A, age, and BMI values (r = 0.138, − 0.001, − 0.145, respectively, all, p > 0.05) and between the Sema3A and age and BMI values (r = − 0.078, − 0.281, respectively, all, p > 0.05). Conclusions: Decreased levels of the anti-inflammatory mediator Sema3A and increased levels of inflammatory mediator IL-6 detected in PXS suggest that these molecules may play a role in systemic manifestations of this syndrome, such as inflammation, atherosclerosis, heart arrhythmia, and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Semaphorin-3A (Sema-3A) is an important immunoregulator protein; it has a role in the maintenance of self-tolerance, so it is thought to be involved in the pathogenesis of many autoimmune diseases such as systemic lupus erythematosus (SLE). The purpose of the study is to assess the possible role of serum Sema-3A level as a potential biomarker for disease activity in patients with SLE and its relation with lupus nephritis. Patients and Methods: We recruited fifty SLE patients and 25 healthy controls. According to the SLE disease activity index (SLEDAI), patients were divided into two groups; active SLE (n = 25) and inactive SLE (n = 25). Sema-3A level was assessed in the study groups using enzyme-linked immunosorbent assay. Laboratory work included antinuclear antibodies, anti-ds-DNA, C3, C4, C-reactive protein, and erythrocyte sedimentation rate (ESR). Results: Serum Sema-3A level was significantly lower among SLE patients compared to healthy controls (18.14 ± 5.77 vs. 65.72 ± 38.08, P < 0.001). Moreover, it was lower among active SLE group compared to inactive group (14.96 ± 4.27 vs. 21.32 ± 5.17, P < 0.001). Serum level of Sema-3A negatively correlated with SLEDAI (P ≤ 0.001) and ESR (P = 0.006) where it was correlated positively with C3 (P ≤ 0.001) and C4 (P = 0.017). Conclusion: SLE activity is associated with decreased serum level of Sema-3A, thus it is suggested that Sema-3A is a candidate to become a useful marker for SLE disease activity.

Background: Semaphorin-3A (Sema-3A) is an important immunoregulator protein; it has a role in the maintenance of self-tolerance, so it is thought to be involved in the pathogenesis of many autoimmune diseases such as systemic lupus erythematosus (SLE). The purpose of the study is to assess the possible role of serum Sema-3A level as a potential biomarker for disease activity in patients with SLE and its relation with lupus nephritis. Patients and Methods: We recruited fifty SLE patients and 25 healthy controls. According to the SLE disease activity index (SLEDAI), patients were divided into two groups; active SLE (n = 25) and inactive SLE (n = 25). Sema-3A level was assessed in the study groups using enzyme-linked immunosorbent assay. Laboratory work included antinuclear antibodies, anti-ds-DNA, C3, C4, C-reactive protein, and erythrocyte sedimentation rate (ESR). Results: Serum Sema-3A level was significantly lower among SLE patients compared to healthy controls (18.14 ± 5.77 vs. 65.72 ± 38.08, P < 0.001). Moreover, it was lower among active SLE group compared to inactive group (14.96 ± 4.27 vs. 21.32 ± 5.17, P < 0.001). Serum level of Sema-3A negatively correlated with SLEDAI (P ≤ 0.001) and ESR (P = 0.006) where it was correlated positively with C3 (P ≤ 0.001) and C4 (P = 0.017). Conclusion: SLE activity is associated with decreased serum level of Sema-3A, thus it is suggested that Sema-3A is a candidate to become a useful marker for SLE disease activity. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a complex disorder of diarthrodial joints caused by multiple risk factors and is characterized by articular cartilage destruction as well as changes in other articular tissues. Semaphorin 3A (Sema3A), known to be a chemo-repellent for sensory nerve fibers, has recently been implicated in cartilage OA pathophysiology. We demonstrated that the expression of SEMA3A and its receptor neuropilin-1 (NRP1) are synchronously upregulated in chondrocytes isolated from knee cartilage of OA patients compared to non-OA control chondrocytes. In addition, we observed that during in vitro passaging of OA chondrocytes, the Nrp-1 level increases, whereas the Sema3A level decreases. In this study, we aimed to uncover how Sema3A-Nrp-1 signaling affects metabolism and viability of OA chondrocytes via siRNA-mediated inhibition of Nrp-1 expression. We observed a decreased proliferation rate and an increase in adhesion and senescence after Nrp-1 silencing. Moreover, MMP13 gene expression was reduced by approximately 75% in NRP1 knockdown OA chondrocytes, whereas MMP13 expression was induced by Sema3A treatment in control (nt siRNA) OA chondrocytes, accompanied by an impaired AKT phosphorylation. These findings suggest a potential catabolic function of Sema3A signaling in OA chondrocytes by inducing MMP13 expression and by compromising pro-survival AKT activation. We propose that targeting the Sema3A-Nrp-1 signaling axis might be an opportunity to interfere with OA pathogenesis and progression. [ABSTRACT FROM AUTHOR]

Neuropilin-1 (Nrp1) encodes the transmembrane cellular receptor neuropilin-1, which is associated with cardiovascular and neuronal development and was within the peak SNP interval on chromosome 8 in our prior GWAS study on age-related hearing loss (ARHL) in mice. In this study, we generated and characterized an inner ear-specific Nrp1 conditional knockout (CKO) mouse line because Nrp1 constitutive knockouts are embryonic lethal. In situ hybridization demonstrated weak Nrp1 mRNA expression late in embryonic cochlear development, but increased expression in early postnatal stages when cochlear hair cell innervation patterns have been shown to mature. At postnatal day 5, Nrp1 CKO mice showed disorganized outer spiral bundles and enlarged microvessels of the stria vascularis (SV) but normal spiral ganglion cell (SGN) density and presynaptic ribbon body counts; however, we observed enlarged SV microvessels, reduced SGN density, and a reduction of presynaptic ribbons in the outer hair cell region of 4-month-old Nrp1 CKO mice. In addition, we demonstrated elevated hearing thresholds of the 2-month-old and 4-month-old Nrp1 CKO mice at frequencies ranging from 4 to 32kHz when compared to 2-month-old mice. These data suggest that conditional loss of Nrp1 in the inner ear leads to progressive hearing loss in mice. We also demonstrated that mice with a truncated variant of Nrp1 show cochlear axon guidance defects and that exogenous semaphorin-3A, a known neuropilin-1 receptor agonist, repels SGN axons in vitro. These data suggest that Neuropilin-1/Semaphorin-3A signaling may also serve a role in neuronal pathfinding in the developing cochlea. In summary, our results here support a model whereby Neuropilin-1/Semaphorin-3A signaling is critical for the functional and morphological integrity of the cochlea and that Nrp1 may play a role in ARHL.

Background and Objective: Identification of biomarkers to assess individual risk and monitor periodontal health status is important. Research on lipocalin‐2 (LCN2) and semaphorin3A (Sema3A) is lacking. This study aimed to evaluate gingival crevicular fluid (GCF) LCN2, Sema3A, and tumor necrosis factor‐α (TNF‐α) levels in periodontally healthy (H), gingivitis (G), and periodontitis (P) patients, and their changes following non‐surgical periodontal therapy. Methods: Sixty systemically healthy and non‐smoker participants, diagnosed as periodontally healthy, gingivitis, and stage III grade C periodontitis, were recruited (n = 20/group). Clinical periodontal parameters were recorded and GCF samples were obtained at baseline from all groups; for group P, these were repeated one and three months following non‐surgical periodontal treatment. GCF LCN2, Sema3A, and TNF‐α levels were evaluated with enzyme‐linked immunosorbent assay. Results: GCF LCN2, Sema3A, and TNF‐α total amounts were significantly higher in disease groups than group H (p <.001). Between P and G groups, only TNF‐α levels were significantly different (p <.001). Non‐surgical periodontal therapy resulted in significant improvement of all clinical parameters and significant decreases of GCF LCN2 and TNF‐α levels, at both time points, compared with baseline (p <.001). Sema3A levels remained unchanged following treatment (p >.05). LCN2 and TNF‐α levels were significantly positively correlated with clinical parameters. LCN2 (AUC [area under the curve] = 0.94) and TNF‐α (AUC = 0.98) levels were similarly accurate in differentiating between periodontal disease (whether G or P) and healthy controls. Conclusions: LCN2 and TNF‐α levels in GCF are correlated with clinical parameters and could prove useful as non‐invasive screening tools for periodontitis. [ABSTRACT FROM AUTHOR]

COPD is an inflammatory disorder caused by prolonged inhalation of harmful substances such as cigarette smoke that leads to an irreversible respiratory disorder. Airway obstruction usually has a progressive period characterized by chronic cough, sputum production, and dyspnea, resulting in decreased physical activity. Two hypotheses have been proposed for the pathogenesis of lung diseases, especially COPD, including the oxidant-antioxidant imbalance hypothesis and the protease-antioxidant imbalance hypothesis. Oxidants can cause irreversible damage to lung cells. Oxidants activate inflammatory gene expression primarily through NFκB signaling. Increase inflammation promotes apoptosis in the epithelial cells, endothelial cells, and airways, that resulting Emphysema. This pathological period causes progress the disease. Recently, has been shown that decreased physical activity is associated with COPD injuries, and the level of physical activity is most associated with COPD mortality. Therefore, the tendency to maintain and improve the physical activity of pulmonary patients, especially COPD was increased. In lung diseases, muscle mass usually decreases and severe atrophy occurs. Most studies suggest increased mobility and exercise to enhance cardiorespiratory endurance and decrease atrophy. However, the exact biological mechanism for the recovery of patients with COPD after a physical activity has not been explained. Exercise can produce Irisin and Semaphorin-3A by stimulating muscle and nerve cell, which have positive effects on other tissues, including the lungs. Limited studies have examined the role of these factors in lung tissue. Therefore, in this mini-review, the lung muscle cross-talk is examined by evaluating the role of Irisin and Semaphorin-3A.

Semaphorin-3A (Sema-3A), a secreted member of the semaphorin family, is well known for playing regulatory functions at all stages of the immune response. Sema-3A transduces signals by binding to its cognate receptors, namely, class A plexins (Plxns A1 to A4) and neuropilin-1 (Nrp-1). The downstream diverse signaling pathways induced by connecting Sema-3A to its receptors were found to be involved in the pathogenesis of different immunological disorders, ranging from cancer to autoimmunity and allergies. Recent studies have demonstrated that Sema-3A expression is diminished in the murine models and patients with allergic rhinitis (AR; a chronic inflammatory disorder of the nasal mucosa), suggesting the involvement of Sema-3A in AR pathogenesis. Investigations also revealed that treatment of these mice with exogenous Sema-3A protein alleviates the clinical symptom scores of AR, thereby compensating for the reduced expression of Sema-3A in AR. Indeed, Sema-3A treatment could suppress allergic responses in AR via inhibiting Th2/Th17 responses and boosting Th1/Treg responses. Also, Sema-3A could diminish dendritic cell (DC) maturation and T cell proliferation. Since it is implicated in the pathogenesis of AR; thus, Sema-3A turns to be a promising tool of therapy to be studied and utilized in this disease. This review intends to highlight the recent evidence on the role of Sema-3A in AR pathogenesis and summarizes the recent findings regarding the expression status of Sema-3A, as well as its therapeutic potential for treating this disease. Highlights: Sema-3A plays regulatory functions at all stages of the immune response. Sema-3A receptors are the class A plexins (A1-A4) and neuropilin-1 (Nrp-1). Sema-3A expression is reduced in murine models and patients with allergic rhinitis. Connecting Sema-3A to Nrp-1 increases Foxp3 expression in Treg cells. Injecting Sema-3A protein exerts therapeutic effects in mouse models of allergic diseases. Sema-3A shows promise as a therapeutic tool for the treatment of allergic rhinitis. [ABSTRACT FROM AUTHOR]

The thymus is responsible for thymocyte differentiation into immunocompetent T lymphocytes. Different cell types in the thymic microenvironment actively cooperate in this process, interacting with the developing thymocytes through soluble factors, extracellular matrix (ECM) molecules, and receptors. In addition, this microenvironment can be influenced by several factors, such as semaphorin-3A (Sema3A), which is a multifunctional protein involved in cell migration. We evaluated the Sema3A effects on the cellular parameters and functional features of thymic stromal cells. Thymic stromal cells were obtained by enzymatic digestion of the murine thymus. These cells were treated with Sema3A and evaluated as follows: cell morphology by scanning electron microscope, F-actin cytoskeleton and deposition of ECM molecules by fluorescence microscopy, and adhesion assays with freshly obtained thymocytes. The obtained thymic stroma was composed of 67% of thymic epithelial cells (TECs), and 90% of the TECs were positive for the Sema3A receptor neuropilin-1. These cells secreted CXCL12, IL-7 and extended thymocyte survival. Sema3A changed the morphology of thymic stromal cells and promoted F-actin reorganization. In addition, the fibronectin fibers were reoriented, and the laminin production was increased in Sema3A-treated thymic stromal cells. In the adhesion assays, there was an increase in the number of adhered thymocytes when thymic stromal cells were pretreated with Sema3A. Our data strongly suggest the active participation of Sema3A in thymic physiology, highlighting its role as an immunomodulatory molecule. This may provide important knowledge for understanding the interactions of thymic cells. [ABSTRACT FROM AUTHOR]

Afferent and efferent cardiac neurotransmission via the cardiac nerves intricately modulates nearly all physiological functions of the heart (chronotropy, dromotropy, lusitropy, and inotropy). Afferent information from the heart is transmitted to higher levels of the nervous system for processing (intrinsic cardiac nervous system, extracardiac-intrathoracic ganglia, spinal cord, brain stem, and higher centers), which ultimately results in efferent cardiomotor neural impulses (via the sympathetic and parasympathetic nerves). This system forms interacting feedback loops that provide physiological stability for maintaining normal rhythm and life-sustaining circulation. This system also ensures that there is fine-tuned regulation of sympathetic-parasympathetic balance in the heart under normal and stressed states in the short (beat to beat), intermediate (minutes to hours), and long term (days to years). This important neurovisceral/autonomic nervous system also plays a major role in the pathophysiology and progression of heart disease, including heart failure and arrhythmias leading to sudden cardiac death. Transdifferentiation of neurons in heart failure, functional denervation, cardiac and extracardiac neural remodeling has also been identified and characterized during the progression of disease. Recent advances in understanding the cellular and molecular processes governing innervation and the functional control of the myocardium in health and disease provide a rational mechanistic basis for the development of neuraxial therapies for preventing sudden cardiac death and other arrhythmias. Advances in cellular, molecular, and bioengineering realms have underscored the emergence of this area as an important avenue of scientific inquiry and therapeutic intervention.

The onset of diabetic nephropathy (DN) is highlighted by glomerular filtration barrier abnormalities. Identifying pathogenic factors and targetable pathways driving DN is crucial to developing novel therapies and improving the disease outcome. Semaphorin3a (sema3a) is a guidance protein secreted by podocytes. Excess sema3a disrupts the glomerular filtration barrier. Here, using immunohistochemistry, we show increased podocyte SEMA3A in renal biopsies from patients with advanced DN. Using inducible, podocyte-specific Sema3a gain-of-function (Sema3a(+)) mice made diabetic with streptozotocin, we demonstrate that sema3a is pathogenic in DN. Diabetic Sema3a(+) mice develop massive proteinuria, renal insufficiency, and extensive nodular glomerulosclerosis, mimicking advanced DN in humans. In diabetic mice, Sema3a(+) exacerbates laminin and collagen IV accumulation in Kimmelstiel-Wilson-like glomerular nodules and causes diffuse podocyte foot process effacement and F-actin collapse via nephrin, αvβ3 integrin, and MICAL1 interactions with plexinA1. MICAL1 knockdown and sema3a inhibition render podocytes not susceptible to sema3a-induced shape changes, indicating that MICAL1 mediates sema3a-induced podocyte F-actin collapse. Moreover, sema3a binding inhibition or podocyte-specific plexinA1 deletion markedly ameliorates albuminuria and abrogates renal insufficiency and the diabetic nodular glomerulosclerosis phenotype of diabetic Sema3a(+) mice. Collectively, these findings indicate that excess sema3a promotes severe diabetic nephropathy and identifies novel potential therapeutic targets for DN.

Astrocytes, the most abundant cells in the central nervous system, promote synapse formation and help to refine neural connectivity. Although they are allocated to spatially distinct regional domains during development, it is unknown whether region-restricted astrocytes are functionally heterogeneous. Here we show that postnatal spinal cord astrocytes express several region-specific genes, and that ventral astrocyte-encoded semaphorin 3a (Sema3a) is required for proper motor neuron and sensory neuron circuit organization. Loss of astrocyte-encoded Sema3a leads to dysregulated α-motor neuron axon initial segment orientation, markedly abnormal synaptic inputs, and selective death of α- but not of adjacent γ-motor neurons. In addition, a subset of TrkA(+) sensory afferents projects to ectopic ventral positions. These findings demonstrate that stable maintenance of a positional cue by developing astrocytes influences multiple aspects of sensorimotor circuit formation. More generally, they suggest that regional astrocyte heterogeneity may help to coordinate postnatal neural circuit refinement.

Background: Semaphorin-3A (Sema3A), as a secreted semaphorin, is an immune modulator molecule participating in the pathogenesis of autoimmune diseases. MicroRNAs (miRNAs) modulate the target-gene expression at the post-transcriptional level. It has been proposed that miRNAs may be crucial to the modulation of the function of semaphorins. Previous findings have proven that miR-497-5p is upregulated and Sema3A is downregulated in some autoimmune disorders. Thus, we aimed to examine the presence of any correlation between Sema3A and miR-497-5p in peripheral blood mononuclear cells (PBMCs). Methods: PBMCs were cultured and transfected with miR-497-5p mimic using the X-tremeGENE™ reagent. The expression level of Sema3A was assessed after 48 hours in supernatants and cells via the enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction, respectively. Cell viability was evaluated using the methylthiazol tetrazolium assay. All the experiments were done in triplicate, and the statistical analyses were performed with SPSS, version 20. P values equal to or less than 0.05 were considered significant.Results: We observed downregulation of the Sema3A gene (P=0.0001) and its secretion (P=0.032) in the PBMCs through miR-497-5p transfection. Moreover, transfection with miR-497-5p mimic and downregulation of Sema3A did not affect the viability of the PBMCs (P=0.061).Conclusion: Based on the obtained results, we suggest that miR-497-5p has a high suppressive effect on Sema3A expression and both Sema3A and miR-497-5p can be considered critical targets for further studies on future therapeutic attempts for the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

Background: Semaphorin-3A (Sema3A) and Semaphorin-7A (Sema7A) play crucial roles in immune system by inhibiting T cell proliferation and leading to the secretion of pro-inflammatory cytokines. Increasing evidence suggest that Sema3A and Sema7A may link to the development and pathogenesis of systemic lupus erythematosus (SLE). Objective: This study aims to evaluate the association of Sema3A, Sema7A gene single-nucleotide polymorphisms (SNPs) with susceptibility to SLE. Methods: There were 495 SLE patients and 493 healthy controls in the study. Sema3A gene and Sema7A gene were genotyped by improved multiple ligase detection reaction (iMLDR), their plasma expression levels were detected by enzyme-linked immunosorbent assay (ELISA). Results: No differences in genotype and allele frequencies of these SNPs were observed between SLE patients and healthy controls. However, analysing Sema3A and Sema7A SNPs with clinical manifestations of SLE indicated that, in Sema3A, the A allele frequencies of rs7804122 polymorphism was higher in patients with oral ulcers. In Sema7A, there were differences in allele frequencies of the rs2075589 and rs28362930 polymorphisms between SLE patients with haematological disorder and those without. The GG genotype and G allele frequencies of rs28362930 and the CC genotype, and C allele frequencies of rs741761 were both related to discoid rash in SLE patients. The allele frequency of G (rs28362930) was higher in SLE patients with renal disorder. There were differences in the genotype frequencies and allele frequencies of rs741761 between SLE patients with and without arthritis. No differences in plasma Sema3A and Sema7A levels were detected in SLE patients of different genotypes. Conclusions: Sema3A and Sema7A gene polymorphisms are not related to SLE genetic susceptibility, but may link to several clinical features of SLE.

Sympathetic nerves innervate most organs and regulate organ blood flow. Specifically, in the uterus, estradiol (E2) elicits rapid degeneration of sympathetic axons and stimulates the growth of blood vessels. Both physiological remodeling processes, critical for reproduction, have been extensively studied but as independent events and are still not fully understood. Here, we examine the neuropilin-1 (NRP1), a shared receptor for axon guidance and angiogenic factors. Systemic estradiol or vehicle were chronically injected to prepubertal rats and uterine and sympathetic chain sections immunostained for NRP1. Uterine semaphorin-3A mRNA was evaluated by in situ hybridization. Control sympathetic uterine-projecting neurons (1-month-old) expressed NRP1 in their somas but not in their intrauterine terminal axons. Estradiol did not affect NRP1 in the distal ganglia. However, at the entrance of the organ, some sympathetic NRP1-positive nerves were recognized. Vascular NRP1 was confined to intrauterine small-diameter vessels in both hormonal conditions. Although the overall pattern of NRP1-IR was not affected by E2 treatment, a subpopulation of infiltrated eosinophil leukocytes showed immunoreactivity for NRP1. Sema3A transcripts were detected in this cellular type as well. No NRP1-immunoreactive axons nor infiltrated eosinophils were visualized in other estrogenized pelvic organs. Together, these data suggest the involvement of NRP1/Sema3A signaling in the selective E2-induced uterine neurovascular remodeling. Our data support a model whereby NRP1 could coordinate E2-induced uterine neurovascular remodeling, acting as a positive regulator of growth when expressed in vessels and as a negative regulator of growth when expressed on axons. [ABSTRACT FROM AUTHOR]

BackgroundThe development of the corticospinal tract (CST) in higher vertebrates relies on a series of axon guidance decisions along its long projection pathway. Several guidance molecules are known to be involved at various decision points to regulate the projection of CST axons. However, previous analyses of the CST guidance defects in mutant mice lacking these molecules have suggested that there are other molecules involved in CST axon guidance that are yet to be identified. In this study, we investigate the role of plexin signaling in the guidance of motor CST axons in vivo.ResultsExpression pattern studies show that plexin-A3, plexin-A4, and neuropilin-1 are expressed in the developing cerebral cortex when the motor CST axons originating from layer V cortical neurons are guided down to the spinal cord. By analyzing mutant mice, we show that motor CST axons that turn dorsally to cross the midline at the pyramidal decussation require plexin-A3 and plexin-A4 signaling. Although other CST guidance defects are found in neuropilin-1 mutants, this dorsal turning defect is not observed in either neuropilin-1 or neuropilin-2 mutants, suggesting that the local cues that activate plexin signaling at the dorsal turning point are membrane-bound semaphorins. Further expression pattern study and mutant analysis indicate that Sema6A is one of the local cues for motor CST axon turning at the pyramidal decussation.ConclusionDorsal turning and midline crossing at the pyramidal decussation is a crucial step to properly direct CST axons into the dorsal spinal cord. We show that the signaling of plexin-A3, plexin-A4, and Sema6A is at least partially required for dorsal turning of the CST axons, while neuropilin-1 is required for proper fasciculation of the tract at midline crossing. Together with previous reports, these results demonstrate that several guidance cues are specifically utilized to regulate the dorsal turning and midline crossing of developing CST axons.

BackgroundThe ability of a neuron to regenerate functional connections after injury is influenced by both its intrinsic state and also by extrinsic cues in its surroundings. Investigations of the transcriptional changes undergone by neurons during in vivo models of injury and regeneration have revealed many transcripts associated with these processes. Because of the complex milieu of interactions in vivo, these results include not only expression changes directly related to regenerative outgrowth and but also unrelated responses to surrounding cells and signals. In vitro models of neurite outgrowth provide a means to study the intrinsic transcriptional patterns of neurite outgrowth in the absence of extensive extrinsic cues from nearby cells and tissues.ResultsWe have undertaken a genome-wide study of transcriptional activity in embryonic superior cervical ganglia (SCG) and dorsal root ganglia (DRG) during a time course of neurite outgrowth in vitro. Gene expression observed in these models likely includes both developmental gene expression patterns and regenerative responses to axotomy, which occurs as the result of tissue dissection. Comparison across both models revealed many genes with similar gene expression patterns during neurite outgrowth. These patterns were minimally affected by exposure to the potent inhibitory cue Semaphorin3A, indicating that this extrinsic cue does not exert major effects at the level of nuclear transcription. We also compared our data to several published studies of DRG and SCG gene expression in animal models of regeneration, and found the expression of a large number of genes in common between neurite outgrowth in vitro and regeneration in vivo.ConclusionMany gene expression changes undergone by SCG and DRG during in vitro outgrowth are shared between these two tissue types and in common with in vivo regeneration models. This suggests that the genes identified in this in vitro study may represent new candidates worthy of further study for potential roles in the therapeutic regrowth of neuronal connections.

Objective Semaphorin-3A (SEMA3A) and its receptors are found on some immune cells and act as suppressors of immune cells over-activation. Considering the role of SEMA3A and its down-regulation in some autoimmune diseases, as well as our bioinformatics predictions, we assumed that miR-145-5p might affect SEMA3A expression. So, we aimed to determine the effect of miR-145-5p on SEMA3A gene expression level. Materials and Methods In this experimental study, we evaluated the effect of miR-145-5p transfection on SEMA3A expression in peripheral blood mononuclear cells (PBMCs) using ELISA and quantitative real-time polymerase chain reaction (PCR) methods. Results Our results showed that miR-145-5p is able to decrease SEMA3A expression at both protein and mRNA levels. These data confirmed our previous bioinformatic prediction about the inhibitory effect of miR-145-5p on SEMA3A expression. Conclusion These results enlightened us about an unknown aspect of SEMA3A role in some autoimmune disorders like multiple sclerosis (MS) and rheumatoid arthritis (RA) and also proposed SEMA3A as a potential therapeutic approach.

Normal tension glaucoma (NTG) is a progressive neurodegenerative disease in glaucoma families. Typical glaucoma develops because of increased intraocular pressure (IOP), whereas NTG develops despite normal IOP. As a subtype of open-angle glaucoma, NTG is characterized by retinal ganglion cell (RGC) degeneration, gradual loss of axons, and injury to the optic nerve. The relationship between glutamate excitotoxicity and oxidative stress has elicited great interest in NTG studies. We recently reported that suppressing collapsin response mediator protein 2 (CRMP2) phosphorylation in S522A CRMP2 mutant (CRMP2 KIKI) mice inhibited RGC death in NTG mouse models. This study evaluated the impact of the natural compounds huperzine A (HupA) and naringenin (NAR), which have therapeutic effects against glutamate excitotoxicity and oxidative stress, on inhibiting CMRP2 phosphorylation in mice intravitreally injected with N-methyl-D-aspartate (NMDA) and GLAST mutant mice. Results of the study demonstrated that HupA and NAR significantly reduced RGC degeneration and thinning of the inner retinal layer, and inhibited the elevated CRMP2 phosphorylation. These treatments protected against glutamate excitotoxicity and suppressed oxidative stress, which could provide insight into developing new effective therapeutic strategies for NTG., (© 2024. The Author(s).)

Neuronal factor semaphorin-3A is viewed as immune suppressant of peripheral T lymphocytes, but it can also negatively affect activity of the thymus, the central organ of the immune system. The study examined the effects of this factor on proliferative activity and apoptosis of mouse thymocytes in vitro. Semaphorin-3A inhibited spontaneous and mitogen-stimulated proliferative activity of thymocytes producing no effect on the development of apoptosis in these cells. Flow cytometry revealed expression of semaphorin-3A receptors neuropilin-1 and plexin-A1 on thymocyte membranes. Approximately 13% thymocytes simultaneously expressed both receptors. The study suggests that semaphorin-3A, which is constitutively synthesized in thymic stroma in vivo, can play the role of inhibitory factor during thymocyte maturation. [ABSTRACT FROM AUTHOR]

Background: Semaphorin-3A (Sema3A) and Semaphorin-7A (Sema7A) play crucial roles in immune system by inhibiting T cell proliferation and leading to the secretion of pro-inflammatory cytokines. Increasing evidence suggest that Sema3A and Sema7A may link to the development and pathogenesis of systemic lupus erythematosus (SLE). Objective: This study aims to evaluate the association of Sema3A, Sema7A gene single-nucleotide polymorphisms (SNPs) with susceptibility to SLE. Methods: There were 495 SLE patients and 493 healthy controls in the study. Sema3A gene and Sema7A gene were genotyped by improved multiple ligase detection reaction (iMLDR), their plasma expression levels were detected by enzyme-linked immunosorbent assay (ELISA). Results: No differences in genotype and allele frequencies of these SNPs were observed between SLE patients and healthy controls. However, analysing Sema3A and Sema7A SNPs with clinical manifestations of SLE indicated that, in Sema3A, the A allele frequencies of rs7804122 polymorphism was higher in patients with oral ulcers. In Sema7A, there were differences in allele frequencies of the rs2075589 and rs28362930 polymorphisms between SLE patients with haematological disorder and those without. The GG genotype and G allele frequencies of rs28362930 and the CC genotype, and C allele frequencies of rs741761 were both related to discoid rash in SLE patients. The allele frequency of G (rs28362930) was higher in SLE patients with renal disorder. There were differences in the genotype frequencies and allele frequencies of rs741761 between SLE patients with and without arthritis. No differences in plasma Sema3A and Sema7A levels were detected in SLE patients of different genotypes. Conclusions:Sema3A and Sema7A gene polymorphisms are not related to SLE genetic susceptibility, but may link to several clinical features of SLE. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy, characterized by cardiomyocyte enlargement, is an adaptive response of the heart to certain hypertrophic stimuli; however, prolonged hypertrophy results in cardiac dysfunction and can ultimately cause heart failure. The present study evaluated the role of semaphorin-3A (Sema3A), a neurochemical inhibitor, in cardiac hypertrophy, utilizing an isoproterenol (ISO) induced H9c2 cell model. Cells were stained with rhodamine-phalloidin to assess the cell surface area and reverse transcription-quantitative PCR was performed to quantify mRNA expression levels of Sema3A, brain natriuretic factor (BNF) and β-myosin heavy chain (β-MHC). The protein expression levels of the autophagy-related proteins light chain 3 (LC3), p62 and Beclin-1, and the Akt/mTOR signaling pathway associated proteins Akt, phosphorylated (p)-Akt, mTOR, p-mTOR, 4E-binding protein 1 (4EBP1) and p-4EBP1 were semi-quantified using western blotting. Rapamycin, a canonical autophagy inducer, was administered to H9c2 cells to elucidate the regulatory mechanism of Sema3A. The results indicated significantly increased cell surface area and elevated BNF and β-MHC mRNA expression levels, increased LC3II/I ratio and Beclin-1 protein expression levels and significantly decreased p62 protein expression levels after treatment of H9c2 cardiomyocytes with ISO for 24 h. Sema3A overexpression improved ISO-induced hypertrophy in H9c2 cells, indicated by decreased cell surface area and reduced BNF and β-MHC mRNA expression levels. Moreover, Sema3A overexpression inhibited ISO-induced autophagy in H9c2 cells, indicated by decreased LC3II/I ratio and Beclin-1 protein expression levels and increased p62 protein expression levels. The autophagy activator rapamycin partially inhibited the protective effect of Sema3A on ISO-induced hypertrophy. Sema3A overexpression suppressed the decrease of the protein expression levels of p-Akt, mTOR and their downstream target 4EBP1, which is induced by ISO. Collectively, these results suggested Sema3A prevented ISO-induced cardiac hypertrophy by inhibiting autophagy via the Akt/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Myelinated axons form long-range connections that enable rapid communication between distant brain regions, but how genetics governs the strength and organization of these connections remains unclear. We perform genome-wide association studies of 206 structural connectivity measures derived from diffusion magnetic resonance imaging tractography of 26,333 UK Biobank participants, each representing the density of myelinated connections within or between a pair of cortical networks, subcortical structures or cortical hemispheres. We identify 30 independent genome-wide significant variants after Bonferroni correction for the number of measures studied (126 variants at nominal genome-wide significance) implicating genes involved in myelination (SEMA3A), neurite elongation and guidance (NUAK1, STRN, DPYSL2, EPHA3, SEMA3A, HGF, SHTN1), neural cell proliferation and differentiation (GMNC, CELF4, HGF), neuronal migration (CCDC88C), cytoskeletal organization (CTTNBP2, MAPT, DAAM1, MYO16, PLEC), and brain metal transport (SLC39A8). These variants have four broad patterns of spatial association with structural connectivity: some have disproportionately strong associations with corticothalamic connectivity, interhemispheric connectivity, or both, while others are more spatially diffuse. Structural connectivity measures are highly polygenic, with a median of 9.1 percent of common variants estimated to have non-zero effects on each measure, and exhibited signatures of negative selection. Structural connectivity measures have significant genetic correlations with a variety of neuropsychiatric and cognitive traits, indicating that connectivity-altering variants tend to influence brain health and cognitive function. Heritability is enriched in regions with increased chromatin accessibility in adult oligodendrocytes (as well as microglia, inhibitory neurons and astrocytes) and multiple fetal cell types, suggesting that genetic control of structural connectivity is partially mediated by effects on myelination and early brain development. Our results indicate pervasive, pleiotropic, and spatially structured genetic control of white-matter structural connectivity via diverse neurodevelopmental pathways, and support the relevance of this genetic control to healthy brain function., (© 2024. The Author(s).)

Spinal cord injury (SCI) often results in various long-term sequelae, and chronically injured spinal cords exhibit a refractory feature, showing a limited response to cell transplantation therapies. To our knowledge, no preclinical studies have reported a treatment approach with results surpassing those of treatment comprising rehabilitation alone. In this study of rats with SCI, we propose a novel combined therapy involving a semaphorin 3A inhibitor (Sema3Ai), which enhances axonal regeneration, as the third treatment element in combination with neural stem/progenitor cell transplantation and rehabilitation. This comprehensive therapeutic strategy achieved significant improvements in host-derived neuronal and oligodendrocyte differentiation at the SCI epicenter and promoted axonal regeneration even in the chronically injured spinal cord. The elongated axons established functional electrical connections, contributing to significant enhancements in locomotor mobility when compared with animals treated with transplantation and rehabilitation. As a result, our combined transplantation, Sema3Ai, and rehabilitation treatment have the potential to serve as a critical step forward for chronic SCI patients, improving their ability to regain motor function., (Copyright © 2024 Yoshida et al.)

Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. ACC is composed of myoepithelial and epithelial neoplastic cells which grow slowly and have a tendency for neural invasion. The long term prognosis is still relatively poor. Although several gene abnormalities, such as fusions involving MYB or MYBL1 oncogenes and the transcription factor gene NFIB, and overexpression of KIT have been reported in ACC, their precise functions in the pathogenesis of ACC remain unclear. We recently demonstrated that the elevated expression of Semaphorin 3A (SEMA3A), specifically expressed in myoepithelial neoplastic cells, might function as a novel oncogene-related molecule to enhance cell proliferation through activated AKT signaling in 9/10 (90%) ACC cases. In the current study, the patient with ACC whose tumor was negative for SEMA3A in the previous study, revisited our hospital with late metastasis of ACC to the cervical lymph node eight years after surgical resection of the primary tumor. We characterized this recurrent ACC, and compared it with the primary ACC using immunohistochemical methods. In the recurrent ACC, the duct lining epithelial cells, not myoepithelial neoplastic cells, showed an elevated Ki-67 index and increased cell membrane expression of C-kit, along with the expression of phosphorylated ERK. Late metastasis ACC specimens were not positive for β-catenin and lymphocyte enhancer binding factor 1 (LEF1), which were detected in the nuclei of perineural infiltrating cells in primary ACC cells. In addition, experiments with the GSK-3 inhibitor revealed that β-catenin pathway suppressed not only KIT expression but also proliferation of ACC cells. Moreover, stem cell factor (SCF; also known as KIT ligand, KITL) induced ERK activation in ACC cells. These results suggest that inactivation of Wnt/β-catenin signaling may promote C-kit-ERK signaling and cell proliferation of in metastatic ACC., Competing Interests: Declaration of Competing Interest None of the authors have any relevant financial relationship(s) with a commercial interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Breast cancer is a major health concern, and its accurate diagnosis and management depend on identifying its histological type and biological subtype. Semaphorin-3A (SEMA3A) is a membrane protein with diverse roles in cellular processes, including cancer progression and angiogenesis regulation. However, its role in breast cancer remains poorly understood. This study aimed to evaluate SEMA3A expression in breast cancer and investigate its distribution across breast cancer subtypes: luminal A, luminal B, HER2-positive, and triple-negative breast cancer (TNBC). Immunohistochemical evaluation was performed on 98 breast cancer patients' tumor specimens, and SEMA3A expression was assessed in tumor cells and vessels. The study included the analysis of the Ki67 proliferation index, estrogen receptor (ER) expression, progesterone receptor (PR) expression, and HER2 status in conjunction with SEMA3A expression. Analysis indicated positive expression of SEMA3A in breast cancer cells in 60 out of 98 cases. SEMA3A expression correlated positively with Ki67 levels in tumor cells (p = 0.0005, R Spearman 0.338). Notably, a negative correlation was found between SEMA3A expression and ER and PR levels in tumor cells (p = 0.04, Spearman's R = - 0.21 and p = 0.016, Spearman's R = - 0.25 respectively). HER2 status did not significantly influence SEMA3A expression. The study demonstrated positive SEMA3A expression in tumor vessels across all subtypes in 91 out of 98 cases, suggesting its involvement in endothelial cell function. However, no significant differences in SEMA3A expression were observed between breast cancer subtypes either in vessels or tumor cells. These findings suggest that elevated SEMA3A expression may be associated with worse prognosis in breast cancer, especially in ER- and PR-negative tumors. Further investigations are warranted to fully comprehend the role of SEMA3A in breast cancer biology, which may lead to the identification of novel therapeutic targets and personalized treatment strategies for breast cancer patients., (© 2024. The Author(s).)

Neonatal hypoxic-ischemic encephalopathy (HIE) is an abnormal neurological condition caused by hypoxic-ischemic damage during the perinatal period. Human placenta derived mesenchymal stem cells (hPMSCs) have been shown to have protective and reparative effects in various neurological diseases; however, the research on HIE is insufficient. This study aimed to establish a rat model of HIE and transplant hPMSCs through the lateral ventricle after hypoxic-ishcemic (HI) brain damage to observe its protective effects and mechanisms, with a focus on brain apoptosis compared among groups. Differentially expressed apoptosis-related proteins were screened using a rat cytokine array and subsequent verification. Neuropilin-1 (NRP-1) and Semaphorin 3A (Sema 3A) were selected for further investigation. Western blotting was used to quantify the expression of Sema 3A and the proteins related to PI3K/Akt/mTOR signaling pathway. Exogenous Sema 3A was added to evaluate the effects of Sema 3A/NRP-1 on hPMSCs following HI injury. hPMSCs transplantation ameliorated HI-induced pathological changes, reduced apoptosis, and improved long-term neurological prognosis. Furthermore, Sema 3A/NRP-1 was a key regulator in reducing HI-induced apoptosis after hPMSCs transplantation. hPMSCs inhibited the expression of Sema 3A/NRP-1 and activated the PI3K/Akt/mTOR signaling pathway. Additionally, exogenous Sema 3A abolished the protective effects of hPMSCs against HI. In conclusion, hPMSCs transplantation reduced apoptosis and improved long-term neurological prognosis after HI by downregulating Sema 3A/NRP-1 expression and activating the PI3K/Akt/mTOR signaling pathway., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Previous studies revealed that progression of multiple myeloma (MM) is associated with downregulation of semaphorin-3A (sema3A) expression in bone marrow endothelial cells. We therefore determined if serum sema3A concentrations are correlated with MM progression and if sema3A can affect MM progression. We find that the concentration of sema3A in sera of MM patients is strongly reduced and that the decrease is correlated with disease progression. A similar depletion is found in patients having acute myeloid leukemia and acute lymphoblastic leukemia but not in cancer forms that do not involve the bone marrow such as in colon cancer. Expression of a modified sema3A [furin-resistant sema3A (FR-sema3A)] stabilized against cleavage by furin-like proprotein convertases in CAG MM cells did not affect their behavior in-vitro. CAG cells injected into the tail vein of severe combined immunodeficient (SCID) mice home to the bone marrow and proliferate, mimicking MM disease progression. Disease progression in mice injected with CAG cells expressing FR-sema3A was inhibited, resulting in prolonged survival and a lower incidence of bone lesions. Histological examination and fluorescence-activated cell sorting analysis revealed that FR-sema3A expression reduced the infiltration of the CAG cells into the bone marrow, reduced bone marrow necrosis and reduced angiogenesis induced by the MM cells in the bone marrow. Our results suggest that measurement of sema3A serum concentrations may be of use for the diagnosis and for the monitoring of malignancies of the bone marrow such as MM. Furthermore, our results suggest that FR-sema3A may perhaps find use as an inhibitor of MM disease progression. [ABSTRACT FROM AUTHOR]

Bone regeneration is impaired in patients with type 2 diabetes mellitus (T2DM), which leads to non-healing after bone loss. The decreased osteogenic capacity of bone mesenchymal stem cells (BMSCs) might be a main reason. Sema3A, as a powerful protein promoting osteocyte differentiation, shows potential for bone regeneration treatment. BMSCs may be a therapeutic solution. In this study, we divided BMSCs from T2DM rats (BMSCs-D) and normal rats (BMSCs-N), identified their ability to differentiate into different cell types. Then we found decreased expression of Sema3A in BMSCs-D compared with BMSCs-N. Stimulating with Sema3A showed no influence in the proliferation or migration of BMSCs. However, Sema3A stimulation significantly increased the expression of osteogenic‑related genes, including type I collagen, alkaline phosphatase, Runt-related transcription factor 2 (RUNX2), bone morphogenetic protein and osteocalcin. Besides, the osteogenic capacity of BMSCs was also increased by Sema3A stimulation. In conclusion, we proved that exogenous Sema3A stimulation might repair the osteogenic capacity of BMSCs-D, thus providing a new strategy for restoring the impaired bone regeneration ability for T2DM patients. [ABSTRACT FROM AUTHOR]

Abstract: Semaphorin-3a (Sema3A), a soluble axon guidance cue, appears to play an important role in the development of acute kidney injury (AKI) and has been regarded as an early diagnostic marker to evaluate the progression of AKI. However, the role of Sema3A in sepsis-associated AKI remains unknown. In this study, lipopolysaccharide (LPS) was used to simulate sepsis-associated AKI and the role of Sema3A in LPS-induced AKI was investigated in vivo and in vitro. In our in vivo study, Sema3A was found in tubular epithelial cells (TECs), which presented a higher level after LPS treatment. Meanwhile, the results of our in vitro experiment showed that Sema3A was also elevated in NRK-52E cells treated by LPS. Notably, inhibition of Sema3A by (−)-epigallocatechin-3-gallate (EGCG) could significantly reduce kidney inflammation and apoptosis in mice. Likewise, EGCG intervention also ameliorated the inflammation and apoptosis of cells in vitro. Furthermore, our research also found that the Rac1/NF-κB p65 and JNK pathways were possibly involved in the Sema3A-mediated inflammation and apoptosis of TECs, respectively. Our findings suggest that Sema3A play a pathogenic role by promoting inflammation and apoptosis of TECs in LPS-induced AKI. It might serve as a useful treatment target in ameliorating sepsis-associated AKI.Key messages: Sema3A is upregulated in LPS-induced AKI.Inhibition of Sema3A attenuates inflammation and apoptosis of TECs in LPS-induced AKI.Sema3A enhances the LPS-induced inflammation of TECs through the Rac1/NF-κB p65 pathway.Sema3A exacerbates the LPS-induced apoptosis of TECs through the JNK pathway. [ABSTRACT FROM AUTHOR]

Autoimmune diseases (ADs) are featured by the body’s immune responses being directed against its own tissues, resulting in prolonged inflammation and subsequent tissue damage. Currently, the exact pathogenesis of ADs remains not fully elucidated. Semaphorin-3A (Sema3A), a secreted member of semaphorin family, is a potent immunoregulator during all immune response stages. Sema3A has wide expression, such as in bone, connective tissue, kidney, neurons, and cartilage. Sema3A can downregulate ADs by suppressing the over-activity of both T-cell and B-cell autoimmunity. Moreover, Sema3A shows the ability to enhance T-cell and B-cell regulatory properties that control ADs, including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and systemic sclerosis. However, it can also induce ADs when overexpressed. Together, these data strongly suggest that Sema3A plays a pivotal role in ADs, and it may be a promising treatment target for these diseases. In the present review, we focus on the immunological functions of Sema3A and summarize recent studies on the involvement of Sema3A in the pathogenesis of ADs; the discoveries obtained from recent findings may translate into novel therapeutic agent for ADs. [ABSTRACT FROM AUTHOR]