Semaphorin Research Articles

SiJunZi decoction ameliorates bone quality and redox homeostasis and regulates advanced glycation end products/receptor for advanced glycation end products and WNT/β-catenin signaling pathways in diabetic mice

Ethnopharmacological relevanceSiJunZi decoction (SJZD), one of the traditional Chinese medicine formulas, has been clinically and traditionally used to improve glucose and lipid metabolism and promote bone remodeling. Aim of the studyTo study the actions and mechanisms of SJZD on bone remodeling in a type 2 diabetes mouse model. Materials and methodsDiabetic mice generated with a high-fat diet (HFD) and streptozotocin (STZ) were subjected to SJZD treatment for 8 weeks. Blood glucose and lipid profile, redox status and bone metabolism were determined by ELISA or biochemical assays. Bone quality was evaluated by micro-CT, three-point bending assay and Fourier transform infrared spectrum (FTIR). Bone histomorphometry alterations were evaluated by Hematoxylin-Eosin (H&E), tartrate resistant acid phosphatase (TRAP) staining and Safranin O-fast green staining. The expressions of superoxide dismutase 1 (SOD1), advanced glycation end products (AGEs), receptor for advanced glycosylation end products (RAGE), phosphorylated nuclear factor kappa-B (p–NF–κB), NF-κB, cathepsin K, semaphorin 3A (Sema3A), insulin-like growth factor 1 (IGF1), p-GSK-3β, (p)-β-catenin, Runt-related transcription factor 2 (Runx2) and Cyclin D1 in the femurs and/or tibias were examined by Western blot or immunohistochemical staining. The main constituents in the SJZD aqueous extract were characterized by a HPLC/MS. ResultsSJZD intervention improved glucose and lipid metabolism and preserved bone quality in the diabetic mice, in particular glucose tolerance, lipid profile, bone microarchitecture, strength and material composition. SJZD administration to diabetic mice preserved redox homeostasis in serum and bone marrow, and prevented an increase in AGEs, RAGE, p–NF–κB/NF-κB, cathepsin K, p-GSK-3β, p-β-catenin expressions and a decrease in Sema3A, IGF1, β-catenin, Runx2 and Cyclin D1 expressions in tibias and/or femurs. Thirteen compounds were identified in SJZD aqueous extract, including astilbin, liquiritin apioside, ononin, ginsenoside Re, Rg1, Rb1, Rb2, Ro, Rb3, Rd, notoginsenoside R2, glycyrrhizic acid, and licoricesaponin B2. ConclusionsSJZD ameliorates bone quality in diabetic mice possibly via maintaining redox homeostasis. The mechanism governing these alterations are possibly related to effects on the AGEs/RAGE and Wnt/β-catenin signaling pathways. SJZD may offer a novel source of drug candidates for the prevention and treatment of type 2 diabetes and osteoporosis.

Single-cell communication patterns and their intracellular information flow in synovial fibroblastic osteoarthritis and rheumatoid arthritis

BackgroundSynovial fibroblasts are critical for maintaining homeostasis in major autoimmune diseases involving joint inflammation, including osteoarthritis and rheumatoid arthritis. However, little is known about the interactions among different cell subtypes and the specific sets of signaling pathways and activities that they trigger. MethodsUsing social network analysis, pattern recognition, and manifold learning approaches, we identified patterns of single-cell communication in OA (osteoarthritis) and RA (rheumatoid arthritis). ResultsOur results suggest that OA and RA have distinct cellular communication patterns and signaling pathways. The LAMININ (Laminin) and COLLAGEN (Collagen) pathways predominate in osteoarthritis, while the EGF (Epidermal growth factor), NT (Neurotrophin) and CDH5 (Cadherin 5) pathways predominate in rheumatoid arthritis, with a central role for THY1 (Thy-1 cell surface antigen) +CDH11 (Cadherin 11) + cells. The OA opens the PDGF (Platelet-derived growth factors) pathway (driver of bone angiogenesis), the RA opens the EGF pathway (bone formation) and the SEMA3 (Semaphorin 3A) pathway (involved in immune regulation). Interestingly, we found that OA no longer has cell types involved in the MHC complex (Major histocompatibility complex) and their activity, whereas the MHC complex functions primarily in RA in the presentation of inflammatory antigens, and that the complement system in OA has the potential to displace the function of the MHC complex. The specific signaling patterns of THY1+CDH11+ cells and their secreted ligand receptors are more conducive to cell migration and lay the foundation for promoting osteoclastogenesis. This subpopulation may also be involved in the accumulation of lymphocytes, affecting the recruitment of immune cells. Members of the collagen family (COL1A1 (Collagen Type I Alpha 1 Chain), COL6A2 (Collagen Type VI Alpha 2 Chain) and COL6A1 (Collagen Type VI Alpha 1 Chain)) and transforming growth factor (TGFB3) maintain the extracellular matrix in osteoarthritis and mediate cell migration and adhesion in rheumatoid arthritis, including the PTN (Pleiotrophin) / THBS1 (Thrombospondin 1) interaction. ConclusionIncreased understanding of the interaction networks between synovial fibroblast subtypes, particularly the shared and unique cellular communication features between osteoarthritis and rheumatoid arthritis and their hub cells, should help inform the design of therapeutic agents for inflammatory joint disease.

Relevance of circulating Semaphorin 4A for rheumatoid arthritis response to treatment

The lack of validated tools to predict rheumatoid arthritis (RA) disease course warrants the development of new reliable biomarkers. Our aim was to evaluate the merit of circulating SEMA4A for the prediction of outcomes in patients with RA. In a first cohort of 101 consecutive RA patients followed up for 41 ± 15 months, increased baseline SEMA4A levels were identified as an independent predictor of treatment failure (hazard ratio, HR 2.71, 95% CI 1.14–6.43), defined by the occurrence of patient-reported flares and initiation or change of targeted therapy. The highest predictive value of treatment failure was obtained with the combination of increased circulating SEMA4A and/or Disease Activity Score (DAS) 28-CRP > 3.2 and/or active synovitis on doppler ultrasound (HR 10.42, 95% CI 1.41–76.94). In a second independent cohort of 40 consecutive RA patients who initiated new therapy because of insufficient disease control, baseline SEMA4A levels were significantly higher in patients who further experienced none or moderate response, and SEMA4A concentrations were markedly decreased in the group of patients with good clinical response as compared to non-responders. Circulating SEMA4A appears as an appealing biomarker in RA with ability to predict treatment failure, and with association with response to therapy.

Comparative Assessment of the Immunological Significance of Semaphorin 5A and Anti-Cyclic Citrullinated Peptide Antibodies in Iraqi Patients with Rheumatoid Arthritis

The objective of this research was to assess the predictive potential of Semaphorin 5A in comparison to Anti-Cyclic Citrullinated Peptide antibodies for forecasting disease progression and treatment responses among Iraqi patients with Rheumatoid Arthritis (RA). Conducted as a case-control study, the investigation encompassed a total of 150 participants, comprising 100 RA patients and 50 healthy individuals. The study took place at Baghdad Teaching Hospital over the period from November 2021 to February 2022. Enrolled participants were selected based on the 2010 criteria established by the American College of Rheumatology. The levels of biomarkers were assessed using the enzyme-linked immunosorbent assay (ELISA) method. The findings demonstrated a noteworthy elevation in the levels of both ACCP and Semaphorin 5A among RA patients compared to the control group (p<0.001). Furthermore, these levels were found to be higher in individuals with active disease as opposed to those with inactive disease. In both active and inactive disease states, the levels of both ACCP and Semaphorin 5A remained considerably higher compared to the levels observed in the healthy control group (p<0.001). In patients who had not undergone treatment, the levels of both ACCP and Semaphorin 5A exhibited considerably greater significance compared to those who received Methotrexate or etanercept (p<0.001). A noteworthy and positive correlation was observed between ACCP and Semaphorin 5A, with a correlation coefficient of 0.476 (p<0.001). The sensitivity for ACCP and Semaphorin 5A was determined to be 72% and 83% respectively, while the specificity values were 98% and 76%. The study's conclusion highlighted the promising prognostic potential of both ACCP and Semaphorin 5A, establishing them as potential biomarkers for distinguishing between Rheumatoid Arthritis patients and healthy individuals. Predict disease activity and response to methotrexate or etanercept. Active disease patients and without treatments patients ACCP and Semaphorin5A levels were higher than inactive and received treatments (methotrexate or etanercept).

A motif in the 5'untranslated region of messenger RNAs regulates protein synthesis in a S6 kinase-dependent manner.

The 5' untranslated regions (UTRs) in messenger RNAs (mRNAs) play an important role in the regulation of protein synthesis. We had previously identified a group of mRNAs that includes human semaphorin 7A (SEMA7A) whose translation is upregulated by the Erk/p90S6K pathway in human eosinophils, with a potential negative impact in asthma and airway inflammation. In the current study, we aimed to find a common 5'UTR regulatory cis-element, and determine its impact on protein synthesis. We identified a common and conserved 5'UTR motif GGCTG-[(C/G)T(C/G)]n-GCC that was present in this group of mRNAs. Mutations of the first two GG bases in this motif in SEMA7A 5'UTR led to a complete loss of S6K activity dependence for maximal translation. In conclusion, the newly identified 5'UTR motif present in SEMA7A has a critical role in regulating S6K-dependent protein synthesis.

RAS‑stimulated release of exosomal miR‑494‑3p promotes the osteolytic bone metastasis of breast cancer cells.

RAS activation is a key determinant of breast cancer progression and metastasis. However, the role of the interaction among exosomes, RAS and microRNAs (miRNAs/miRs) in the osteolytic bone metastasis of breast cancer remains unclear. Therefore, the present study aimed to examine the role of activated RAS (KRAS, HRAS and NRAS) in the release of exosome‑mediated osteoclastogenic miRNAs and to elucidate their functional role in bone microenvironment remodeling invitro and invivo. Exosomes derived from RAS‑activated breast cancer cells promoted RANKL‑induced osteoclastogenesis; however, RAS inhibition abolished this effect. miR‑494‑3p, miR‑4508 and miR‑6869‑5p were identified as osteoclastogenic miRNAs in the exosomes secreted by RAS‑activated breast cancer cells. The levels of these osteoclastogenic miRNAs in the sera of patients with human epidermal growth factor receptor 2‑positive luminal breast cancer were significantly higher than those in the sera of patients with triple‑negative breast cancer. miR‑494‑3p exhibited both osteoclastogenic and anti‑osteoblastogenic activity. Treatment with a miR‑494‑3p inhibitor abolished the exosome‑mediated increase in RANKL‑induced osteoclastogenesis. Treatment with a miR‑494‑3p mimic enhanced RANKL‑induced osteoclast formation; however, treatment with its inhibitor suppressed this effect by targeting leucine‑rich repeat‑containing G‑protein coupled receptor 4 in osteoclast precursors. Furthermore, miR‑494‑3p inhibited bone morphogenetic protein 2‑induced osteoblast formation by targeting semaphorin 3A. In a mouse model, exosomes derived from breast cancer cells promoted osteolytic bone lesions; however, treatment with a miR‑494‑3p inhibitor significantly suppressed this effect. On the whole, the present study provides a novel mechanism, demonstrating that the RAS activation of breast cancer cells induces osteolytic bone metastasis by stimulating the exosome‑mediated transfer of osteoclastogenic miRNAs, including miR‑494‑3p to bone cells.

High-quality genome assemblies provide clues on the evolutionary advantage of blue peafowl over green peafowl

An intriguing example of differential adaptability is the case of two Asian peafowl species, Pavo cristatus (blue peafowl) and Pavo muticus (green peafowl), where the former has a “Least Concern” conservation status and the latter is an “Endangered” species. To understand the genetic basis of this differential adaptability of the two peafowl species, a comparative analysis of these species is much needed to gain the genomic and evolutionary insights. Thus, we constructed a high-quality genome assembly of blue peafowl with an N50 value of 84.81 Mb (pseudochromosome-level assembly), and a high-confidence coding gene set to perform the genomic and evolutionary analyses of blue and green peafowls with 49 other avian species. The analyses revealed adaptive evolution of genes related to neuronal development, immunity, and skeletal muscle development in these peafowl species. Major genes related to axon guidance such as NEO1 and UNC5, semaphorin (SEMA), and ephrin receptor showed adaptive evolution in peafowl species. However, blue peafowl showed the presence of 42% more coding genes compared to the green peafowl along with a higher number of species-specific gene clusters, segmental duplicated genes and expanded gene families, and comparatively higher evolution in neuronal and developmental pathways. Blue peafowl also showed longer branch length compared to green peafowl in the species phylogenetic tree. These genomic insights obtained from the high-quality genome assembly of P. cristatus constructed in this study provide new clues on the superior adaptability of the blue peafowl over green peafowl despite having a recent species divergence time.

Semaphorin 7a regulates inflammatory mediators and permeability in retinal endothelial cells

Research supports a key role for inflammation in damaging the retinal vasculature. Current work is designed to investigate regulation of key inflammatory pathways. In this study, we hypothesized that semaphorin 7a (Sema7a) was involved in the increased inflammatory mediators and permeability changes in retinal endothelial cells (REC) grown in high glucose. For these studies, we used diabetic mouse samples and REC to investigate our hypothesis. Primary retinal endothelial cells were grown in normal (5 mM) or high glucose (25 mM glucose) for measurements. In a subset of cells grown in high glucose, cells were transfected with Sema7a siRNA or scrambled siRNA. We measured levels of key inflammatory mediators and zonula occludens-1 (ZO-1) and occludin levels by Western blot. Data suggest that high glucose increased inflammatory mediators and reduced the tight junction proteins, which follows what is often observed in cells grown in high glucose. Sema7a siRNA significantly decreased inflammatory proteins and increased levels of ZO-1 and occludin. These data suggest that Sema7a mediates the actions of high glucose in REC. Use of Sema7a siRNA may offer a new avenue for treatment.

SEMA7a primes integrin α5β1 engagement instructing fibroblast mechanotransduction, phenotype and transcriptional programming

Integrins are cellular receptors that bind the extracellular matrix (ECM) and facilitate the transduction of biochemical and biophysical microenvironment cues into cellular responses. Upon engaging the ECM, integrin heterodimers must rapidly strengthen their binding with the ECM, resulting in the assembly of force-resistant and force-sensitive integrin associated complexes (IACs). The IACs constitute an essential apparatus for downstream signaling and fibroblast phenotypes. During wound healing, integrin signaling is essential for fibroblast motility, proliferation, ECM reorganization and, ultimately, restoration of tissue homeostasis. Semaphorin 7A (SEMA7a) has been previously implicated in post-injury inflammation and tissue fibrosis, yet little is known about SEMA7a's role in directing stromal cell, particularly fibroblast, behaviors. We demonstrate that SEMA7a regulates integrin signaling through cis-coupling with active integrin α5β1 on the plasma membrane, enabling rapid integrin adhesion strengthening to fibronectin (Fn) and normal downstream mechanotransduction. This molecular function of SEMA7a potently regulates fibroblast adhesive, cytoskeletal, and migratory phenotype with strong evidence of downstream alterations in chromatin structure resulting in global transcriptomic reprogramming such that loss of SEMA7a expression is sufficient to impair the normal migratory and ECM assembly phenotype of fibroblasts resulting in significantly delayed tissue repair in vivo.

MiR-196b-5p Regulates Osteoblast and Osteoclast Differentiation and Bone Homeostasis by Targeting SEMA3A.

miR-196b-5p plays a role in various malignancies. We have recently reported its function in regulating adipogenesis. However, it remains to be clarified whether and how miR-196b-5p affects bone cells and bone homeostasis. In this study, in vitro functional experiments showed an inhibitory effect of miR-196b-5p on osteoblast differentiation. Mechanistic explorations revealed that miR-196b-5p directly targeted semaphorin 3a (Sema3a) and inhibited Wnt/β-catenin signaling. SEMA3A attenuated the impaired osteogenesis induced by miR-196b-5p. Osteoblast-specific miR-196b transgenic mice showed significant reduction of bone mass. Trabecular osteoblasts were reduced and bone formation was suppressed, whereas osteoclasts, marrow adipocytes, and serum levels of bone resorption markers were increased in the transgenic mice. The osteoblastic progenitor cells from the transgenic mice had decreased SEMA3A levels and exhibited retarded osteogenic differentiation, whereas those marrow osteoclastic progenitors exhibited enhanced osteoclastogenic differentiation. miR-196b-5p and SEMA3A oppositely regulated the expression of receptor activator of nuclear factor-κB ligand and osteoprotegerin. The calvarial osteoblastic cells expressing the transgene promoted osteoclastogenesis, whereas the osteoblasts overexpressing Sema3a inhibited it. Finally, in vivo transfection of miR-196b-5p inhibitor to the marrow reduced ovariectomy-induced bone loss in mice. Our study has identified that miR-196b-5p plays a key role in osteoblast and osteoclast differentiation and regulates bone homeostasis. Inhibition of miR-196b-5p may be beneficial for amelioration of osteoporosis. © 2023 American Society for Bone and Mineral Research (ASBMR).

WED-439 - A heterozygous N559Y mutation in Semaphorin 7A promotes non-alcoholic fatty liver disease progression through induction of hepatic ROS production and inflammation

WED-439 - A heterozygous N559Y mutation in Semaphorin 7A promotes non-alcoholic fatty liver disease progression through induction of hepatic ROS production and inflammation

Intravenous Semaphorin 3A Administration Maintains Cardiac Contractility and Improves Electrical Remodeling in a Mouse Model of Isoproterenol-Induced Heart Failure.

The effects of recombinant semaphorin 3A (Sema3A) on myocardial contractility and electrical remodeling in mice with isoproterenol (ISP) -induced heart failure were investigated.C57BL/6J mice intraperitoneally received ISP (480 mg/kg/day, ISP group; n = 24) or saline (control group; n = 31) for 14 days. Twenty-one ISP-treated mice received 0.5 mg/kg Sema3A intravenously on days 7 and 11 (ISP+Sema3A group). The sympathetic nervous system was activated upon ISP treatment, but was reduced upon Sema3A administration. Greater myocardial tissue fibrosis was observed in the ISP group than in the control group. However, fibrosis was not significantly different between the ISP+Sema3A and control groups. Fractional shortening of the left ventricle was lower in the ISP group than in the control group and was restored in the ISP+Sema3A group (control, 53 ± 8%; ISP, 37 ± 7%; ISP+Sema3A, 48 ± 3%; P < 0.05). Monophasic action potential duration at 20% repolarization (MAPD20) was prolonged in the ISP group (compared to control group), but this was reversed upon Sema3A administration (control, 29 ± 3 ms; ISP, 35 ± 6 ms; ISP+Sema3A, 29 ± 3 ms; P < 0.05). qPCR revealed Kv4.3, KChIP2, and SERCA2 downregulation in the ISP group and upregulation in the ISP+Sema3A group; however, Western blotting revealed similar changes only for Kv4.3 (P < 0.05).Intravenous Sema3A may maintain myocardial contractility by suppressing the sympathetic innervation of the myocardium and reducing myocardial tissue damage, in addition to restoring MAPD via Kv4.3 upregulation.

Sodium Valproate Enhances Semaphorin 3A-mediated Anti-angiogenesis and Tumor Growth Inhibition in Human Osteosarcoma Cells.

Class 3 semaphorins, including semaphorin 3A (SEMA3A), are known endogenous angiogenesis inhibitors associated with endothelial cell migration and proliferation, and have been identified in many cancer cells. SEMA3A suppresses tumor angiogenesis by competing with VEGF, but tumors are known to have active angiogenesis, suggesting that expression of SEMA3A and its receptors is epigenetically restrained. To overcome this condition, we aimed to use histone deacetylase (HDAC) inhibitors to enhance the SEMA3A expression in osteosarcoma (OS) cells, thereby suppressing angiogenesis and inhibiting their proliferation and metastasis. OS cell lines and human microvascular endothelial (HMVE) cells were treated with HDAC inhibitors such as sodium valproate (VPA) and Trichostatin A (TSA). Changes in the SEMA3A expression and its related receptors at the mRNA and protein levels, as well as the inhibitory effects on tumor angiogenesis, were investigated. VPA and TSA increased the expression of SEMA3A and its receptor NRP1, without inducing PLXNA1 in OS cells. Similarly, SEMA3A and NRP1 expression was increased in HMVE cells, but no growth inhibition was observed. Furthermore, SEMA3A induced by VPA in OS cell culture medium inhibited vascular tube formation of HMVE cells, and overexpression of SEMA3A enhanced OS cell growth inhibition. This growth-inhibitory effect of SEMA3A induced G1/S cell cycle arrest in OS cells. HDAC inhibitors have anti-angiogenic and anti-tumor activities that may be, in part, mediated via the SEMA3A/NRP1/PLXNA1 autocrine and paracrine pathways.

Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8+ T cell cytotoxicity and proliferation.

Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive non-small cell lung cancer (NSCLC) responded significantly better to anti-programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8+ T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy.

Evaluation of mRNA markers in differentiating human SH-SY5Y cells for estimation of developmental neurotoxicity

Current guidelines for developmental neurotoxicity (DNT) evaluation are based on animal models. These have limitations so more relevant, efficient and robust approaches for DNT assessment are needed. We have used the human SH-SY5Y neuroblastoma cell model to evaluate a panel of 93 mRNA markers that are frequent in Neuronal diseases and functional annotations and also differentially expressed during retinoic acid-induced differentiation in the cell model. Rotenone, valproic acid (VPA), acrylamide (ACR) and methylmercury chloride (MeHg) were used as DNT positive compounds. Tolbutamide, D-mannitol and clofibrate were used as DNT negative compounds. To determine concentrations for exposure for gene expression analysis, we developed a pipeline for neurite outgrowth assessment by live-cell imaging. In addition, cell viability was measured by the resazurin assay. Gene expression was analyzed by RT-qPCR after 6 days of exposure during differentiation to concentrations of the DNT positive compounds that affected neurite outgrowth, but with no or minimal effect on cell viability. Methylmercury affected cell viability at lower concentrations than neurite outgrowth, hence the cells were exposed with the highest non-cytotoxic concentration. Rotenone (7.3 nM) induced 32 differentially expressed genes (DEGs), ACR (70 µM) 8 DEGs, and VPA (75 µM) 16 DEGs. No individual genes were significantly dysregulated by all 3 DNT positive compounds (p < 0.05), but 9 genes were differentially expressed by 2 of them. Methylmercury (0.8 nM) was used to validate the 9 DEGs. The expression of SEMA5A (encoding semaphorin 5A) and CHRNA7 (encoding nicotinic acetylcholine receptor subunit α7) was downregulated by all 4 DNT positive compounds. None of the DNT negative compounds dysregulated any of the 9 DEGs in common for the DNT positive compounds. We suggest that SEMA5A or CHRNA7 should be further evaluated as biomarkers for DNT studies in vitro since they also are involved in neurodevelopmental adverse outcomes in humans.

Semaphorin 3A levels in vascular and nonvascular phenotypes in systemic sclerosis.

Semaphorin 3A (Sema3A) plays a regulatory role in immune responses. The aim of this study was to evaluate Sema3A levels in patients with systemic sclerosis (SSc), especially in major vascular involvements such as digital ulcer (DU), scleroderma renal crisis (SRC), pulmonary arterial hypertension (PAH), and to compare Sema3A level with SSc disease activity. In SSc patients, patients with DU, SRC, or PAH were grouped as major vascular involvements and those without as nonvascular, and Sema3A levels were compared between the groups and with a healthy control group. The Sema3A levels and acute phase reactants in SSc patients, as well as their association with the Valentini disease activity index and modified Rodnan skin score, were evaluated. The Sema3A values (mean ± SD) were 57.60 ± 19.81ng/mL in the control group (n=31), 44.32 ± 5.87ng/mL in patients with major vascular involvement SSc (n=21), and 49.96 ± 14.00ng/mL in the nonvascular SSc group (n= 35). When all SSc patients were examined as a single group, the mean Sema3A value was significantly lower than controls (P=.016). The SSc with major vascular involvement group had significantly lower Sema3A levels than SSc with nonmajor vascular involvement group (P=.04). No correlation was found between Sema3A, acute phase reactants, and disease activity scores. Also, no relationship was observed between Sema3A levels and diffuse (48.36 ± 11.47ng/mL) or limited (47.43 ± 12.38ng/mL) SSc types (P = .775). Our study suggests that Sema3A may play a significant role in the pathogenesis of vasculopathy and can be used as a biomarker in SSc patients with vascular complications such as DU and PAH.

Sema3A inactivates the ERK/JNK signalling pathways to alleviate inflammation and oxidative stress in lipopolysaccharide-stimulated rat endothelial cells and lung tissues

Semaphorin 3A (Sema3A) is a secretory member of the semaphorin family of immune response regulators. This research focuses on its effects on inflammation and oxidative stress in acute respiratory distress syndrome (ARDS). By analysing the GEO dataset GSE57011, we obtained Sema3A as the most downregulated gene in ARDS samples. Lipopolysaccharide (LPS) was used to stimulate rat pulmonary microvascular endothelial cells (PMVECs) and rats to induce ARDS-like symptoms in vitro and in vivo, respectively. LPS induced severe damage in rat lung tissues, in which reduced immunohistochemical staining of Sema3A was detected. Sema3A overexpression reduced apoptosis and angiogenesis of LPS-induced PMVECs and alleviated lung injury and pulmonary edoema of rats. Moreover, ELISA results showed that Sema3A overexpression downregulated the levels of inflammatory cytokines and oxidative stress markers both in PMVECs and the rat lung. Activation of ERK/JNK signalling aggravated LPS-induced damage on PMVECs; however, the aggravation was partly blocked by Sema3A, which suppressed phosphorylation of ERK/JNK. Overall, this study demonstrates that Sema3A inactivates the ERK/JNK signalling to ameliorate inflammation and oxidative stress in LPS-induced ARDS models. Sema3A might therefore represent a candidate option for ARDS treatment.

The role of Wnt, ARL4C, and Sema3A in developmental process and disease pathogenesis.

Various types of tumors, including malignant and benign ones, occur in the oral cavity. These arise from the mucosal epithelium, odontogenic epithelium, and salivary gland. To date, few major driver events in oral tumors have been identified. Accordingly, molecular targets in anti-tumor therapy for oral tumors are lacking. We focused on elucidating the function of aberrantly activated signal transduction related to oral tumor formation, especially in oral squamous cell carcinoma, ameloblastoma, and adenoid cystic carcinoma, which are raised as common oral tumors. Wnt/β-catenin-dependent pathway is involved in the developmental process, organ homeostasis and disease pathogenesis through regulating various cellular functions by enhancing transcriptional activity. Recently, we identified ADP-ribosylation factor (ARF)-like 4c (ARL4C) and Semaphorin 3A (Sema3A), the expression of which is regulated by Wnt/β-catenin-dependent pathway, and characterized their functions in the developmental process and tumor formation. This review highlights the recent advances in understanding the roles of Wnt/β-catenin-dependent pathway, ARL4C and Sema3A, as determined by pathological and experimental studies.

Contribution of the dihydropyrimidinase-like proteins family in synaptic physiology and in neurodevelopmental disorders.

The dihydropyrimidinase-like (DPYSL) proteins, also designated as the collapsin response mediators (CRMP) proteins, constitute a family of five cytosolic phosphoproteins abundantly expressed in the developing nervous system but down-regulated in the adult mouse brain. The DPYSL proteins were initially identified as effectors of semaphorin 3A (Sema3A) signaling and consequently involved in regulation of growth cone collapse in young developing neurons. To date, it has been established that DPYSL proteins mediate signals for numerous intracellular/extracellular pathways and play major roles in variety of cellular process including cell migration, neurite extension, axonal guidance, dendritic spine development and synaptic plasticity through their phosphorylation status. The roles of DPYSL proteins at early stages of brain development have been described in the past years, particularly for DPYSL2 and DPYSL5 proteins. The recent characterization of pathogenic genetic variants in DPYSL2 and in DPYSL5 human genes associated with intellectual disability and brain malformations, such as agenesis of the corpus callosum and cerebellar dysplasia, highlighted the pivotal role of these actors in the fundamental processes of brain formation and organization. In this review, we sought to establish a detailed update on the knowledge regarding the functions of DPYSL genes and proteins in brain and to highlight their involvement in synaptic processing in later stages of neurodevelopment, as well as their particular contribution in human neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASD) and intellectual disability (ID).

072 Down-regulation of semaphorin 4A in keratinocytes can reflect the disease-associated features in non-lesional skin of psoriasis

072 Down-regulation of semaphorin 4A in keratinocytes can reflect the disease-associated features in non-lesional skin of psoriasis