OBJECTIVE: To explore the role of semaphorin 4D (Sema4D) in immunoglobulin A (IgA) -mediated immune abnormalities in B lymphocytes of pediatric Henoch-Schonlein purpura (HSP). METHODS: One hundred HSP children admitted to Hengshui People's Hospital from January 2022 to January 2023 were selected as HSP group, and one hundred healthy children as control group. Sema4D expression was detected, and the relationship between Sema4D expression in children's serum and skin lesions and clinical characteristics of children was analyzed. Sema4D expression on the surface of lymphocytes of HSP children was detected. Different concentrations of human recombinant Sema4D protein was used to stimulate peripheral blood mononuclear cells in HSP children in vitro. The expression level of IgA in the supernatant was detected to verify whether Sema4D mediates immune abnormalities through IgA secreted by B lymphocytes. RESULTS: The Sema4D level in the HSP group was significantly higher than that in the control group (P <0.001). Sema4D level in HSP children with severe, renal involvement, and joint involvement was higher than those with mild to moderate disease, and no renal or joint involvement (all P <0.001). Compared with control group, IgA level, CD8 ⁺ T lymphocyte proportion, and CD19 ⁺ B lymphocyte proportion in the HSP group were significantly higher but CD4 ⁺ T lymphocyte proportion was lower (all P <0.001). The expression levels of Sema4D on the surface of CD4 ⁺ T lymphocytes, CD8 ⁺ T lymphocytes, and CD19 ⁺ B lymphocytes in the HSP group were significantly higher than those in the control group (all P <0.001). With the increase of human recombinant Sema4D protein concentration, the level of IgA expression in HSP children gradually increased (P <0.05). Correlation analysis showed that Sema4D was significantly positively correlated with IgA (r =0.667). CONCLUSION HSP children show high expression of Sema4D, especially on the surface of T and B lymphocytes. The shedding of Sema4D from membrane surface may stimulate B lymphocytes to secrete IgA by binding to CD72, leading to immune abnormalities.
Humans ; IgA Vasculitis/immunology* ; Semaphorins/metabolism* ; B-Lymphocytes/metabolism* ; Immunoglobulin A/immunology* ; Child ; Antigens, CD/metabolism* ; Male ; Female ; Child, Preschool

OBJECTIVES: To establish a prognostic model for primary liver cancer (PLC) using bioinformatics methods. METHODS: Based on the data from 404 patients in the Cancer Genome Atlas (TCGA) database, we constructed a prognostic model integrating the differentially expressed genes, anoikis, and immune-related genes (DAIs) using univariate Cox regression and the LASSO-Cox approach. The predictive ability of the model was evaluated using Kaplan-Meier method and receiver-operating characteristic curves, and a nomogram was developed to facilitate its clinical applications. Gene set enrichment analysis (GSEA) was performed to explore the associated pathways and relationship between the DAIs and the tumor immune microenvironment, and the half-maximal inhibitory concentration (IC₅₀) of liver cancer drugs was calculated using the "pRRophetic" R package. We also detected the expression of SEMA7A in paired tumor and adjacent tissues from liver cancer patients. RESULTS: We constructed and validated a prognostic model based on 7 DAIs (NR4A3, SEMA7A, IL11, AR, BIRC5, EGF, and SPP1), and obtained consistent results in both the TCGA training cohort and GEO validation cohort (GSE14520), where the patients in the low-risk group were characterized by more favorable clinical outcomes and immune status. By integrating this prognostic signature with clinical information, a composite nomogram was generated. Somatic mutation analysis showed that TTN, TP53, and CTNNB1 mutations accounted for the largest proportion of total mutations, and the patients in the low-risk-low-TMB group had higher survival rate. Drug sensitivity analysis revealed differences in sensitivity to chemotherapeutic agents between high- and low-risk groups and between TP53 mutations and non-mutations. In clinical tissue specimens, SEMA7A expression was significantly higher in liver cancer tissues than in the adjacent tissues. CONCLUSIONS We established a new prognostic model based on DAIs for predicting clinical outcomes and therapeutic response of patients with primary liver cancer.
Humans ; Liver Neoplasms/diagnosis* ; Prognosis ; Anoikis ; Nomograms ; Computational Biology ; Tumor Microenvironment ; Semaphorins/metabolism*

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling. Here, we focused on the role of Semaphorin 3A (Sema3A), expressed by sensory nerves, in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement (OTM) model. Firstly, bone formation was activated after the 3rd day of OTM, coinciding with a decrease in sensory nerves and an increase in pain threshold. Sema3A, rather than nerve growth factor (NGF), highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM. Moreover, in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells (hPDLCs) within 24 hours. Furthermore, exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload. Mechanistically, Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway, maintaining mitochondrial dynamics as mitochondrial fusion. Therefore, Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation, both as a pain-sensitive analgesic and a positive regulator for bone formation.
Humans ; Bone Remodeling ; Cell Differentiation ; Osteogenesis ; Semaphorin-3A/pharmacology* ; Trigeminal Ganglion/metabolism*

BACKGROUND: Exploring the underlying mechanism of rituximab resistance is critical to improve the outcomes of patients with diffuse large B-cell lymphoma (DLBCL). Here, we tried to identify the effects of the axon guidance factor semaphorin-3F (SEMA3F) on rituximab resistance as well as its therapeutic value in DLBCL. METHODS: The effects of SEMA3F on the treatment response to rituximab were investigated by gain- or loss-of-function experiments. The role of the Hippo pathway in SEMA3F-mediated activity was explored. A xenograft mouse model generated by SEMA3F knockdown in cells was used to evaluate rituximab sensitivity and combined therapeutic effects. The prognostic value of SEMA3F and TAZ (WW domain-containing transcription regulator protein 1) was examined in the Gene Expression Omnibus (GEO) database and human DLBCL specimens. RESULTS: We found that loss of SEMA3F was related to a poor prognosis in patients who received rituximab-based immunochemotherapy instead of chemotherapy regimen. Knockdown of SEMA3F significantly repressed the expression of CD20 and reduced the proapoptotic activity and complement-dependent cytotoxicity (CDC) activity induced by rituximab. We further demonstrated that the Hippo pathway was involved in the SEMA3F-mediated regulation of CD20. Knockdown of SEMA3F expression induced the nuclear accumulation of TAZ and inhibited CD20 transcriptional levels via direct binding of the transcription factor TEAD2 and the CD20 promoter. Moreover, in patients with DLBCL, SEMA3F expression was negatively correlated with TAZ, and patients with SEMA3F low TAZ high had a limited benefit from a rituximab-based strategy. Specifically, treatment of DLBCL cells with rituximab and a YAP/TAZ inhibitor showed promising therapeutic effects in vitro and in vivo . CONCLUSION Our study thus defined a previously unknown mechanism of SEMA3F-mediated rituximab resistance through TAZ activation in DLBCL and identified potential therapeutic targets in patients.
Humans ; Animals ; Mice ; Rituximab/therapeutic use* ; Hippo Signaling Pathway ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Prognosis ; Semaphorins/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Membrane Proteins/genetics* ; Nerve Tissue Proteins/genetics*

Nonspecific low back pain is closely associated with afferent nerve ingrowth into degenerated IVDs and increasing the inflammatory response. Members of the class 3 semaphorins signal their response through two prominent receptors; the NRP (Neuropilin-1) and the Plexin A. Sema3A (Semaphorin3A) is primarily known for their role in modulating neuronal survival as well as neurite outgrowth and guidance via regulation of Sema3A-NRP-1-plexinA signal pathway. Also, sema3A is shown to be conductive to innervate the inner painful degenerated IVDs (Intervertebral discs). Furthermore, sema3A is thought to act as a barrier to endothelial cells survival and migration on vascular endothelial growth factor (VEGF) and inhibition of KLF5-induced (Krüppel-like factor 5) inflammatory mediators within degenerated IVDs. Therefore, Sema3A produce a new perspective of dual-action therapeutic agent for attenuating the regulator of innervation and angiogenesis into degenerated IVDs and inhibition of KLF5-induced inflammation.
Endothelial Cells ; Humans ; Low Back Pain ; Neuropilin-1 ; Semaphorin-3A ; Vascular Endothelial Growth Factor A

OBJECTIVE: To investigate expression of Semaphorin 3A in rats after spinal cord injury and explore possible mechanism of inhibiting of axonal regeneration after SCI. METHODS: Forty healthy female SD rats, 8 weeks old, weighing (210.00±9.88) g, were randomly divided into control group(20 rats in group A) and model group(20 rats in group B). In control group, removal of T RESULTS: After a simple spinal cord transection injury, hemorrhagic necrosis, localized edema, neurodegeneration, necrosis, and cyst formation occurred in the injured area, and glial scar formation occurred in glial cells. Semaphorin 3A expression levels in control group was low in the gray matter area. There was no expression of Semaphorin 3A in the injured area of spinal cord injury in model group 3 days after operation. On the 14th day, the expression of Semaphorin 3A in the injured area of spinal cord injury increased significantly and was at a high level. On the 28th day, the expression of Semaphorin 3A was moderate. On the 42th day, the positive expression of Semaphorin 3A returned to normal level. CONCLUSION The increased expression of Semaphorin 3A after spinal cord injury may be one of the mechanisms that inhibit axonal regeneration.
Animals ; Female ; Rats ; Rats, Sprague-Dawley ; Semaphorin-3A/genetics* ; Spinal Cord ; Spinal Cord Injuries/genetics*

Child ; Developmental Disabilities/genetics* ; Frameshift Mutation ; Humans ; Seizures/genetics* ; Seizures, Febrile/genetics* ; Semaphorins/genetics*

OBJECTIVE: To measure the level of serum Semaphorin 3A (Sema3A) and to analyze the relationship between serum Sema3A and systemic lupus erythematosus (SLE) with thrombocytopenia. METHODS: The concentration of serum Sema3A was detected by enzyme-linked immuno sorbent assay (ELISA) in 170 SLE patients, 50 Sjögren's syndrome (SS) patients, 19 hypersplenism (HS) patients and 150 healthy controls (HC). Based on the presence of thrombocytopenia and whether the thrombocytopenia was in remission, the SLE patients were divided into three groups: SLE with thrombocytopenia (41 cases), SLE with thrombocytopenia remission (28 cases), and SLE without thrombocytopenia (101 cases). According to whether there was thrombocytopenia, the SS patients were divided into SS with thrombocytopenia (18 cases) and SS without thrombocytopenia (32 cases). The 28 SLE patients who underwent bone marrow aspiration biopsy were divided into two groups from the aspect of whether the bone marrow hyperplasia was normal (19 cases) or low (9 cases), as well as from the aspect of whether the maturity disturbance of megakaryocyte was positive (8 cases) or negative (20 cases). The serum Sema3A levels in SLE, SS, HS with HC were compared, meanwhile, the correlation between serum Sema3A level and platelet (PLT) in the patients with different diseases analyzed. RESULTS: (1) Serum Sema3A levels in SLE were significantly lower than in HC [(3.84±2.76) μg/L vs. (6.96±2.62) μg/L, P < 0.001], serum Sema3A levels in SS were also obviously lower than in HC [(4.35±3.57) μg/L vs. (6.96±2.62) μg/L, P < 0.001], and in HS it was lower than HC at a certain extant [(5.67±2.26) μg/L vs. (6.96±2.62) μg/L, P=0.041]. (2) Serum Sema3A levels in SLE were slightly lower than in SS, but there was no significant difference [(3.84±2.76) μg/L vs. (4.35±3.57) μg/L, P=0.282]. However, when compared with HS, serum Sema3A levels in SLE were significantly lower [(3.84±2.76) μg/L vs. (5.67±2.26) μg/L, P=0.006]. (3) Serum Sema3A concentration in SLE with thrombocytopenia was significantly lower than in SLE with thrombocytopenia remission [(1.28±1.06) μg/L vs. (3.83±2.65) μg/L, P < 0.001], and in SLE patients without thrombocytopenia [(1.28±1.06) μg/L vs. (4.87±2.60) μg/L, P < 0.001]. There was no significant difference between SLE with thrombocytopenia remission and SLE without thrombocytopenia [(3.83±2.65) μg/L vs. (4.87±2.600 μg/L, P=0.123]. Serum Sema3A concentration in SLE with thrombocytopenia was slightly lower than in SS with thrombocytopenia, but there was no significant difference [(1.28±1.06) μg/L vs. (1.68±1.11) μg/L, P=0.189]. (4) Strong positive correlations were found between serum Sema3A and PLT in SLE (r=0.600, P < 0.001). Positive correlations were also found between serum Sema3A and PLT in SS (r=0.573, P < 0.001). However, there was no such correlation showed in HS patients (P=0.393). (5) There was no significant difference of serum Sema3A concentration in SLE whether the bone marrow hyperplasia was normal or low. And the same situation appeared in the patients whether the maturity disturbance of megakaryocyte was positive or negative (P>0.05). CONCLUSION Serum Sema3A was significantly reduced in SLE patients, and it was highly correlated with the blood damage. Similar conclusions could be drawn in patients with SS. The serum level of Sema3A was generally decreasing in desmosis which merged thrombocytopenia, and was obviously positive correlated with platelet counts.
Enzyme-Linked Immunosorbent Assay ; Humans ; Lupus Erythematosus, Systemic/complications* ; Semaphorin-3A ; Sjogren's Syndrome ; Thrombocytopenia/etiology*

OBJECTIVE: To explore the genetic basis for three patients with development delay and to correlate their clinical phenotypes with genetic findings. METHODS: The karyotypes of the probands and their parents were analyzed by conventional G-banding. Chromosomal microarray analysis (CMA) was used to detect microdeletion and microduplication. RESULTS: No kartotypic abnormality was detected in the patients and their parents. CMA analysis identified a de novo 3.10 Mb deletion on chromosome 15q24.1q24.2 in case 1, a de novo 3.14 Mb deletion at 15q24.1q24.2 in case 2, and a 3.13 Mb deletion at 15q24.1q24.2 in case 3. All deletions have encompassed the CPLX3,SEMA7A and SIN3A genes. CONCLUSION The three patients were diagnosed with 15q24 microdeletion syndrome. CPLX3,SEMA7A and SIN3A may be the key genes responsible for this syndrome.
Adaptor Proteins, Signal Transducing ; genetics ; Antigens, CD ; genetics ; Child ; Chromosome Deletion ; Chromosome Disorders ; genetics ; Chromosomes, Human, Pair 15 ; genetics ; GPI-Linked Proteins ; genetics ; Humans ; Intellectual Disability ; genetics ; Repressor Proteins ; genetics ; Semaphorins ; genetics

Psoriasis is a chronic, recurrent, heterogeneous, cutaneous inflammatory skin disease for which there is no cure. It affects approximately 7.5 million people in the United States. Currently, several biologic agents that target different molecules implicated in the pathogenic processes of psoriasis are being assessed in diverse clinical studies. However, relapse usually occurs within weeks or months, meaning there is currently no cure for psoriasis. Therefore, recent studies have discovered diverse new potential treatments for psoriasis: inhibitors of bacteria such as Staphylococcus aureus, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and neuropilin 1 (NRP1). A promising approach that has recently been described involves modifying antimicrobial peptides to develop new cutaneous anti-bacterial agents that target inflammatory skin disease induced by Staphylococcus. Increased expression of TRAIL and its death receptors DR4 and DR5 has been implicated in the pathogenesis of plaque psoriasis. In addition, TRAIL has the ability to inhibit angiogenesis by inducing endothelial cell death and by negative regulation of VEGF-induced angiogenesis via caspase-8-mediated enzymatic and non-enzymatic functions. Since NRP1 regulates angiogenesis induced by multiple signals, including VEGF, ECM and semaphorins, and also initiates proliferation of keratinocytes through NF-κB signaling pathway in involved psoriatic skin, targeting NRP1 pathways may offer numerous windows for intervention in psoriasis. In this review, we will focus on the current knowledge about the emerging role of synthetic antimicrobial peptides, TRAIL and NRP1 blocking peptides in the pathogenesis and treatment of psoriasis.
Anti-Bacterial Agents ; Bacteria ; Biological Factors ; Endothelial Cells ; Keratinocytes ; Necrosis ; Neuropilin-1 ; Peptides ; Psoriasis ; Receptors, Death Domain ; Recurrence ; Semaphorins ; Skin ; Skin Diseases ; Staphylococcus ; Staphylococcus aureus ; Therapeutic Uses ; TNF-Related Apoptosis-Inducing Ligand ; United States ; Vascular Endothelial Growth Factor A