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miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non-Cell-Autonomous Mechanism in ALS.

Axon degeneration and disruption of neuromuscular junctions (NMJs) are key events in amyotrophic lateral sclerosis (ALS) pathology. Although the disease's etiology is not fully understood, it is thought to involve a non-cell-autonomous mechanism and alterations in RNA metabolism. Here, we identified reduced levels of miR126-5p in presymptomatic ALS male mice models, and an increase in its targets: axon destabilizing Type 3 Semaphorins and their coreceptor Neuropilins. Using compartmentalized in vitro cocultures, we demonstrated that myocytes expressing diverse ALS-causing mutations promote axo…

[Correlation analysis of Sema4D with rheumatoid arthritis disease activity, bone destruction and rheumatoid arthritis-related interstitial lung disease].

Objective: To explore the correlation between Semaphorin 4D (Sema4D) and rheumatoid arthritis (RA) clinical manifestations, laboratory indexes, bone destruction and rheumatoid arthritis related interstitial lung disease(RA-ILD), and to analyze its significance in evaluating the severity of patients with rheumatoid arthritis. Methods: A total of 108 RA patients and 50 healthy controls from September 2018 to October 2019 were collected from the Department of Rheumatology and Immunology, Peking University People's Hospital and Beijing Haidian Hospital. According to the DAS 28 score, RA patients w

Semaphorin3A/neuropilin-1 signaling acts as a molecular switch regulating neural crest migration during cornea development.

Cranial neural crest cells migrate into the periocular region and later contribute to various ocular tissues including the cornea, ciliary body and iris. After reaching the eye, they initially pause before migrating over the lens to form the cornea. Interestingly, removal of the lens leads to premature invasion and abnormal differentiation of the cornea. In exploring the molecular mechanisms underlying this effect, we find that semaphorin3A (Sema3A) is expressed in the lens placode and epithelium continuously throughout eye development. Interestingly, neuropilin-1 (Npn-1) is expressed by perio

Biallelic variants of SEMA3F are associated with nonsyndromic hearing loss.

It is crucial to manage hearing loss and its associated public health impacts. In this study, we aimed to understand the role of Sema3f in the development and maintenance of the auditory system. Inner ear-specific Sema3f knockout mice exhibited hearing loss at 8 weeks with an elevated threshold for auditory brainstem response and an absent threshold for distortion product optoacoustic emission tests. Additionally, an increased number of outer hair cells and abnormal patterns of spiral ganglion neuron projections in the outer hair cell regions were observed. Through the analyses of sequencing d

Neuronal guidance factor Sema3A inhibits neurite ingrowth and prevents chondrocyte hypertrophy in the degeneration of knee cartilage in mice, monkeys and humans.

Osteoarthritis (OA) is a degenerative joint disease accompanied with the loss of cartilage and consequent nociceptive symptoms. Normal articular cartilage maintains at aneural state. Neuron guidance factor Semaphorin 3A (Sema3A) is a membrane-associated secreted protein with chemorepulsive properties for axons. However, the role of Sema3A in articular cartilage is still not clear. In the present studies, we investigated the functions of Sema3A in OA development in mice, non-human primates, and patients with OA. Sema3A has a protective effect on cartilage degradation, validated by the organoid

Rectifying the Crosstalk between the Skeletal and Immune Systems Improves Osteoporosis Treatment by Core-Shell Nanocapsules.

Contemporary osteoporosis treatment often neglects the intricate interactions among immune cells, signaling proteins, and cytokines within the osteoporotic microenvironment. Here, we developed core-shell nanocapsules composed of a cationized lactoferrin core and an alendronate polymer shell. By tuning the size of these nanocapsules and leveraging the alendronate shell, we enabled precise delivery of small interfering RNA targeting the Semaphorin 4D gene (siSema4D) to specific bone sites. This strategy integrates the antiresorptive drug alendronate with siSema4D, efficiently inhibiting osteocla

Inhibition of RANKL and Sema4D improves residual ridge resorption in mice.

Residual ridge resorption (RRR) is a chronic and progressive bone resorption following tooth loss. It causes deterioration of the oral environments and leads to the pathogenesis of various systemic diseases. However, the molecular mechanisms and risk factors for RRR progression are still unclear and controversial. In this study, we developed a tooth extraction model using mice for analyzing long-term morphological and gene expression changes in the alveolar bone. We further applied ovariectomy to this model to elucidate the effects of osteoporosis on RRR progression. As a result, the alveolar

A genome-wide screen for variants influencing certolizumab pegol response in a moderate to severe rheumatoid arthritis population.

Certolizumab pegol (CZP) is a PEGylated Fc-free tumor necrosis factor (TNF) inhibitor antibody approved for use in the treatment of rheumatoid arthritis (RA), Crohn's disease, psoriatic arthritis, axial spondyloarthritis and psoriasis. In a clinical trial of patients with severe RA, CZP improved disease symptoms in approximately half of patients. However, variability in CZP efficacy remains a problem for clinicians, thus, the aim of this study was to identify genetic variants predictive of CZP response. We performed a genome-wide association study (GWAS) of 302 RA patients treated with CZP in

PlexinA4 distribution in the adult rat spinal cord and dorsal root ganglia.

PlexinsA1-A4 participate in class 3 semaphorin signaling as co-receptors to neuropilin 1 and 2, PlexinA4 being the latest member of the PlexinA subfamily to be identified. Little is known about the cellular distribution of PlexinA4 in the spinal cord and dorsal root ganglion (DRG). Here, immunohistochemical studies using antibodies to PlexinA4 revealed immunolabeling in neurons in both dorsal and, to a greater extent, ventral horns of the spinal cord. Ventral horn PlexinA4 positive neurons exhibited morphology, size, and location consistent with both motor neurons and interneurons. Labeling wa

Neuro-associated SEMA3C+ tumour cells promote gastric cancer peritoneal metastasis via EBF2-FGF7-FGFR2-mediated tumour-endothelial crosstalk.

BACKGROUND: Recent studies have established that the nervous system is not merely a bystander in tumour progression but can actively remodel the tumour microenvironment through the neuro-tumour axis, thereby promoting tumour invasion, metastasis and survival. Semaphorin 3C (SEMA3C) has been reported to regulate tumour migration, angiogenesis and immune suppression, highlighting its potential role in tumour progression. Although the neuro-tumour axis has been identified in multiple cancer types, its role and underlying mechanisms in gastric cancer peritoneal metastasis (GCPM) remain unclear. M

SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface.

Genetic polymorphisms are associated with the development of nonalcoholic fatty liver disease (NAFLD). Semaphorin7a (Sema7a) deficiency in mouse peritoneal macrophages reduces fatty acid (FA) oxidation. Here, we identified 17 individuals with SEMA7A heterozygous mutations in 470 patients with biopsy-proven NAFLD. SEMA7A heterozygous mutations increased susceptibility to NAFLD, steatosis severity, and NAFLD activity scores in humans and mice. The Sema7aR145W mutation (equivalent to human SEMA7AR148W) significantly induced small lipid droplet accumulation in mouse livers compared with WT mouse l

SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD).

Background: The mutation frequencies of pituitary transcription factors genes in patients with combined pituitary hormone deficiencies (CPHD) vary substantially between populations. However, apart from PROP1 the mutation rate of other genes is low and for almost half of the patients with CPHD the routine sequencing of known genes is unsuccessful in the identification of genetic causes. Methods: A cohort of 66 sporadic and nine familial CPHD cases (80 patients in total) were subjected to initial testing of the genes PROP1, POU1F1, LHX3, LHX4, and HESX1 using a targeted gene panel and MLPA. In p

Совершенствование иммунотерапии клеток ИНКТ путем интеграции оптимизированных эндодоменов ЦАР и участников ИНКТ.

Клетки ИНКТ становятся весьма перспективной платформой иммунотерапии для лечения рака. Чтобы максимально увеличить антираковую активность CAR-INKT против рака крови, мы изучили оптимальные конструкции CAR и их комбинацию с новыми специфичными участниками INKT. Мы находим, что среди пяти различных эндодомен ЦАР, подкрепляемых возросшей вспыльчивостью и перекрестным разговором между Plexin D1 на CAR-INKT и Semaphorin 4 A на клетках миэломы, BCMA CD28z CAR-INKT проявляет наибольшую активность против миэломы. В частности, CD28z CAR-INKT опережает их коллег CAR-T. В целях расширения потенциала CAR-

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… Induction of inflammation and fibrosis by semaphorin 4A in systemic sclerosis. Arthritis Rheumatol. 71 , 1711–1722 (2019). 27. Kumanogoh, A. & Kikutani, H. Immunological functions of the neuropilins and plexins as receptors for semaphorins. Nat. Rev. Immunol. 13 , 802–814 (2013). 28. Gay, C. … Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501 , 252–256 (2013). 41. Naito, Y. et al. Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8(+) T cell cytotoxicity and proliferation. Sci. …

Astrocyte SEMA3C reduction improves Rett Syndrome phenotypes.

During typical neurodevelopment, astrocytes secrete proteins that support neuronal connectivity. This process is disrupted in Rett Syndrome (RTT), a regressive neurodevelopmental disorder characterized by motor, sensory, and cognitive impairments. While astrocytes typically promote neuron outgrowth, co-culture of RTT astrocytes with wildtype neurons inhibits their outgrowth, implicating secreted astrocyte factors in RTT pathology. However, the specific factors and their contributions to RTT deficits remain poorly defined. To address this, we focused on the class 3 semaphorin SEMA3C, which show

Tissue-Targeted Transcriptomics Reveals SEMA3D Control of Hypoglossal Nerve Projection to Mouse Tongue Primordia.

The mouse hypoglossal nerve originates in the occipital motor nuclei at embryonic day (E)10.5 and projects a long distance, reaching the vicinity of the tongue primordia, the lateral lingual swellings, at E11.5. However, the details of how the hypoglossal nerve correctly projects to the primordia are poorly understood. To investigate the molecular basis of hypoglossal nerve elongation, we used a novel transcriptomic approach using the ROKU method. The ROKU algorithm identified 3825 genes specific for lateral lingual swellings at E11.5, of which 34 genes were predicted to be involved in axon gu

SEMA3C promotes thyroid cancer via the Wnt/β-catenin pathway.

Semaphorin 3C (SEMA3C) regulates the progression of several tumors. However, the role of SEMA3C in thyroid cancer remains unknow. In the present study, SEMA3C was overexpressed or knocked down in thyroid cancer cell lines BCPAP and IHH-4. It was found that SEMA3C promoted the cell migration, invasion, and mesenchymal-epithelial transition (EMT) process. SEMA3C overexpression enhanced tumor cell stemness, while SEMA3C knockdown showed the opposite effects. In vivo experiments suggested that SEMA3C accelerated the tumor growth and metastasis. Moreover, SEMA3C enhanced β-catenin nuclear transloca

Plexin B3 guides axons to cross the midline in vivo.

During the development of neural circuits, axons are guided by a variety of molecular cues to navigate through the brain and establish precise connections with correct partners at the right time and place. Many axon guidance cues have been identified and they play pleiotropic roles in not only axon guidance but also axon fasciculation, axon pruning, and synaptogenesis as well as cell migration, angiogenesis, and bone formation. In search of receptors for Sema3E in axon guidance, we unexpectedly found that Plexin B3 is highly expressed in retinal ganglion cells of zebrafish embryos when retinal

Retinopathy of prematurity: A review of pathophysiology and signaling pathways.

Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina and a leading cause of visual impairment and childhood blindness worldwide. The disease is characterized by an early stage of retinal microvascular degeneration, followed by neovascularization that can lead to subsequent retinal detachment and permanent visual loss. Several factors play a key role during the different pathological stages of the disease. Oxidative and nitrosative stress and inflammatory processes are important contributors to the early stage of ROP. Nitric oxide synthase and arginase play important r

Cardiopulmonary bypass changes the plasma proteome in children undergoing tetralogy of Fallot repair.

INTRODUCTION: Cardiopulmonary bypass (CPB) can be associated with deleterious clinical effects. However, the impact of CPB on inflammatory, immunological and other homeostatic pathways remains poorly understood. We investigated the impact of CPB on the plasma proteome in children undergoing tetralogy of Fallot repair. METHODS: Blood samples were taken from 20 children prior to and at the end of CPB and 6h, 12h and 24h after CPB. Plasma was analysed by liquid chromatography-mass spectrometry (LC-MS) in a label-free, untargeted approach. Data were analysed using Genedata software to identify pe

A methylation study implicates the rewiring of brain neural circuits during puberty in the emergence of sex differences in depression symptoms.

BACKGROUND: Women are 1.5-3 times more likely to suffer from depression than men. This sex bias first emerges during puberty and then persis … d genes coding for members of each of the major classes of axon guidance molecules (netrins, slits, semaphorins, ephrins, and cell adhesion molecules). Many of these genes were previously implicated in rodent studies of brain development and depression-like phenotypes, as well as human methylation, gene expression and GWAS studies. CONCLUSIONS: Our study sug …